Combination therapy strategies in engineered Lu radiopharmaceuticals beyond single modality: design principles and application outlet.
1/5 보강
Lu has attracted substantial attention in recent years as a medical radionuclide.
APA
Zhu Y, Zhong G, et al. (2026). Combination therapy strategies in engineered Lu radiopharmaceuticals beyond single modality: design principles and application outlet.. Cell communication and signaling : CCS, 24(1). https://doi.org/10.1186/s12964-026-02700-x
MLA
Zhu Y, et al.. "Combination therapy strategies in engineered Lu radiopharmaceuticals beyond single modality: design principles and application outlet.." Cell communication and signaling : CCS, vol. 24, no. 1, 2026.
PMID
41612421 ↗
Abstract 한글 요약
Lu has attracted substantial attention in recent years as a medical radionuclide. It emits both β-particles (maximum energy 0.497 MeV) and γ-rays (113/208 keV), which provides unique advantages for theranostic applications in oncology. Since the U.S. Food and Drug Administration (FDA) approved [Lu]Lu-DOTA-TATE in 2018, Lu-based radiopharmaceuticals have demonstrated significant clinical value in the targeted treatment of neuroendocrine tumors (NETs) and prostate cancer. However, monotherapy still faces major challenges, including tumor heterogeneity, drug resistance, and dose-related toxicity. These limitations hinder the full therapeutic potential of Lu radiopharmaceuticals. Combination therapy has therefore emerged as a promising strategy to address these obstacles. This review provides a systematic overview of the preparation techniques, clinical efficacy, and combination therapy approaches involving Lu radiopharmaceuticals, with the aim of offering a theoretical foundation and practical guidance for optimizing therapeutic paradigms.
🏷️ 키워드 / MeSH 📖 같은 키워드 OA만
같은 제1저자의 인용 많은 논문 (5)
- Direct Oral Anticoagulants for Cancer-Associated Venous Thromboembolism in Hematologic Malignancies: A Comprehensive Review.
- TARDBP upregulates GJB2 to promote tumor progression in hepatocellular carcinoma.
- Propranolol enhances the oncolytic effect of newcastle disease virus on canine mammary tumor cell by modulating the IFN-I-mediated JAK-STAT signaling pathway.
- [Rapid determination of venetoclax in plasma by ultra performance liquid chromatography-tandem mass spectrometry].
- DHL-11, a novel prieurianin-type limonoid isolated from , targeting IMPDH2 to inhibit triple-negative breast cancer.
📖 전문 본문 읽기 PMC JATS · ~78 KB · 영문
Introduction
Introduction
According to data published in CA Cancer J Clin [1], nearly 20 million new cancer cases and 9.7 million cancer-related deaths occurred worldwide in 2022, making cancer one of the leading causes of mortality globally. Over the past two decades, radionuclide therapy (RNT) has achieved significant breakthroughs in precision oncology [2, 3]. Radiopharmaceuticals can deliver radionuclides to tumor cells in a targeted manner, where the radionuclides subsequently decay and emit radiation to achieve therapeutic or imaging effects. To monitor therapeutic response and enable timely treatment adjustments, Bentzen et al. first introduced the concept of theranostics into radiotherapy planning in 2005 [4], The application of theranostics in nuclear medicine further established the principle of “see what you treat.” As a medical radionuclide, 177Lu has a half-life of 6.65 days and emits both β-particles (maximum energy 0.497 MeV) and γ-rays (113 and 208 keV) [5, 6] These dual emissions endow 177Lu with combined therapeutic and imaging capabilities, making it an ideal theranostic radionuclide. The β-particles have a limited tissue penetration range, thereby reducing damage to surrounding healthy tissues, while the γ-rays enable real-time monitoring of radiopharmaceutical distribution through single-photon emission computed tomography (SPECT). Chemically, 177Lu exhibits high stability when coordinated with bifunctional chelators such as DOTA [7], ensuring reliable in vivo stability of radiolabeled compounds. Since the U.S. FDA approved the clinical use of [177Lu]Lu-DOTA-TATE in 2018 [8], the development of 177Lu radiopharmaceuticals has expanded rapidly, yielding promising therapeutic outcomes in multiple cancers, particularly thyroid cancer, neuroendocrine tumors, and breast cancer [9–11]. Despite these advances, monotherapy with 177Lu radiopharmaceuticals still faces several limitations. Therefore, integrating 177Lu therapy with other treatment modalities represents a promising strategy for achieving enhanced therapeutic efficacy.
According to data published in CA Cancer J Clin [1], nearly 20 million new cancer cases and 9.7 million cancer-related deaths occurred worldwide in 2022, making cancer one of the leading causes of mortality globally. Over the past two decades, radionuclide therapy (RNT) has achieved significant breakthroughs in precision oncology [2, 3]. Radiopharmaceuticals can deliver radionuclides to tumor cells in a targeted manner, where the radionuclides subsequently decay and emit radiation to achieve therapeutic or imaging effects. To monitor therapeutic response and enable timely treatment adjustments, Bentzen et al. first introduced the concept of theranostics into radiotherapy planning in 2005 [4], The application of theranostics in nuclear medicine further established the principle of “see what you treat.” As a medical radionuclide, 177Lu has a half-life of 6.65 days and emits both β-particles (maximum energy 0.497 MeV) and γ-rays (113 and 208 keV) [5, 6] These dual emissions endow 177Lu with combined therapeutic and imaging capabilities, making it an ideal theranostic radionuclide. The β-particles have a limited tissue penetration range, thereby reducing damage to surrounding healthy tissues, while the γ-rays enable real-time monitoring of radiopharmaceutical distribution through single-photon emission computed tomography (SPECT). Chemically, 177Lu exhibits high stability when coordinated with bifunctional chelators such as DOTA [7], ensuring reliable in vivo stability of radiolabeled compounds. Since the U.S. FDA approved the clinical use of [177Lu]Lu-DOTA-TATE in 2018 [8], the development of 177Lu radiopharmaceuticals has expanded rapidly, yielding promising therapeutic outcomes in multiple cancers, particularly thyroid cancer, neuroendocrine tumors, and breast cancer [9–11]. Despite these advances, monotherapy with 177Lu radiopharmaceuticals still faces several limitations. Therefore, integrating 177Lu therapy with other treatment modalities represents a promising strategy for achieving enhanced therapeutic efficacy.
Lu radiopharmaceutical preparation technology
177Lu radiopharmaceutical preparation technology
Radiopharmaceuticals typically consist of a radionuclide and a targeted carrier, and are often supplemented with chelating agents to enhance binding stability [12] (Fig. 1). The design of 177Lu radiopharmaceuticals involves three key components: targeted carrier selection, chelator optimization, and radiolabeling procedures.Targeted carriers mainly include antibodies, peptides, and small molecules, each offering distinct advantages. Antibodies exhibit high specificity and strong binding affinity, however, their large molecular weight adversely impacts pharmacokinetics [13–17]. Peptides provide superior tumor penetration and diffusion, and the clinical response rate of [177Lu]Lu-DOTA-TATE is approximately 43% [18–21]. Small molecules, in contrast, enable rapid tissue penetration and faster systemic clearance, offering additional flexibility for radiopharmaceutical development [22–24].
For chelating agents, DOTA exhibits excellent thermodynamic stability (Kd < 10⁻²³), making it particularly suitable for antibody labeling [25–27], whereas DTPA offers faster radiolabeling kinetics despite its comparatively lower stability [28, 29].
The radiolabeling efficiency of 177Lu complexes is influenced by several critical parameters, including pH, temperature, reaction time, and radionuclide concentration [30, 31]. The pH of the reaction solution affects chelator coordination by altering protonation states. Moderate temperature elevation can accelerate chelation, but excessive heat may increase the dissociation rate. Appropriate reaction time is required to ensure complete labeling while avoiding product degradation. Additionally, radionuclide concentration must be carefully controlled to balance reaction kinetics with final product quality [32, 33].
By optimizing these parameters in a coordinated manner, both labeling efficiency and radiochemical purity can be markedly improved, thereby establishing a solid foundation for the preparation of safe and effective 177Lu radiopharmaceuticals.
Radiopharmaceuticals typically consist of a radionuclide and a targeted carrier, and are often supplemented with chelating agents to enhance binding stability [12] (Fig. 1). The design of 177Lu radiopharmaceuticals involves three key components: targeted carrier selection, chelator optimization, and radiolabeling procedures.Targeted carriers mainly include antibodies, peptides, and small molecules, each offering distinct advantages. Antibodies exhibit high specificity and strong binding affinity, however, their large molecular weight adversely impacts pharmacokinetics [13–17]. Peptides provide superior tumor penetration and diffusion, and the clinical response rate of [177Lu]Lu-DOTA-TATE is approximately 43% [18–21]. Small molecules, in contrast, enable rapid tissue penetration and faster systemic clearance, offering additional flexibility for radiopharmaceutical development [22–24].
For chelating agents, DOTA exhibits excellent thermodynamic stability (Kd < 10⁻²³), making it particularly suitable for antibody labeling [25–27], whereas DTPA offers faster radiolabeling kinetics despite its comparatively lower stability [28, 29].
The radiolabeling efficiency of 177Lu complexes is influenced by several critical parameters, including pH, temperature, reaction time, and radionuclide concentration [30, 31]. The pH of the reaction solution affects chelator coordination by altering protonation states. Moderate temperature elevation can accelerate chelation, but excessive heat may increase the dissociation rate. Appropriate reaction time is required to ensure complete labeling while avoiding product degradation. Additionally, radionuclide concentration must be carefully controlled to balance reaction kinetics with final product quality [32, 33].
By optimizing these parameters in a coordinated manner, both labeling efficiency and radiochemical purity can be markedly improved, thereby establishing a solid foundation for the preparation of safe and effective 177Lu radiopharmaceuticals.
Lu clinical manifestations of radiopharmaceuticals
177Lu clinical manifestations of radiopharmaceuticals
177Lu clinical efficacy and survival benefit analysis
177Lu-labeled radioligands have demonstrated substantial value in tumor therapy (Table 1). Their therapeutic efficacy, survival benefits, and comparative advantages over other treatment modalities have been validated in multiple studies [24, 47, 48]. The following sections systematically summarize their preclinical efficacy, clinical outcomes, and comparative performance relative to other treatment strategies.
Advances in preclinical efficacy research
In recent years, 177Lu-labeled targeted radiopharmaceuticals have exhibited significant antitumor efficacy and favorable safety profiles in preclinical oncology studies. Yang et al. developed [177Lu]Lu-LuFL, a fibroblast activation protein (FAP)–targeted radioligand that demonstrated potent therapeutic efficacy in HT-1080-FAP–positive mouse models. The radioligand markedly inhibited tumor growth, and tumor volumes in the high-dose group (24.05 MBq) were significantly reduced compared with controls. Meanwhile, treated mice maintained stable body weight (0.92–1.17 fold change), and histopathological analysis showed no observable organ damage (Fig. 2A) [44]. Notably, Luna-Gutiérrez et al. developed [177Lu]Lu-DOTA-PD-L1-i, which showed promising therapeutic potential in mouse models of metastatic lung cancer. This radioligand selectively eliminated PD-L1–positive tumor cells and achieved a tumor radiation dose of 43 mGy/MBq—ten times higher than the kidney dose and fifty times higher than the liver dose (Fig. 2B). Its tumor retention time reached 346.5 h (Fig. 2C), suggesting a highly effective precision radiotherapy approach for immune-resistant tumors [45]. Advances in dual-targeting strategies have further broadened the therapeutic capabilities of 177Lu radiopharmaceuticals. Zha et al. developed [177Lu]Lu-P17-079, a dual-targeting radioligand capable of simultaneously recognizing PSMA-positive tumors and bone metastatic lesions. The radioligand achieved an uptake of 14.7% ID/g in PSMA-positive tumors, comparable to [177Lu]Lu-PSMA-617 (14.5% ID/g), and displayed an uptake of 6.52% ID/g in bone lesions—12.5-fold higher than [177Lu]Lu -617 (0.52% ID/g). This dual-targeting capability provides a more comprehensive radiotherapeutic approach for advanced prostate cancer and represents a promising candidate for next-generation radiopharmaceutical development following Pluvicto® [39].
Clinical efficacy
Clinical studies have confirmed that 177Lu-labeled radioligands exhibit distinctive response patterns in the treatment of solid tumors. For example, in the final analysis of the NETTER-1 trial, the combination of [177Lu]Lu-DOTA-TATE and long-acting octreotide yielded a median overall survival (OS) of 48.0 months in patients with advanced midgut neuroendocrine tumors (NETs), extending OS by 11.7 months compared to high-dose long-acting octreotide monotherapy (36.3 months; hazard ratio 0.84, 95% confidence interval 0.60–1.17; p = 0.30), although the difference lacked statistical significance. Long-term safety profiles were consistent with the known side effects, showing manageable hematologic toxicities and gastrointestinal symptoms, with no new safety signals. These findings underscore the clinically meaningful survival benefits and favorable tolerability of [177Lu]Lu-DOTA-TATE, confirming its potential role in this patient population [49]. The NETTER-2 Phase III clinical trial further demonstrated that patients receiving [177Lu]Lu-DOTA-TATE treatment achieved an objective response rate (ORR) of 43%, significantly higher than the control group’s 9.3% [18]. Particularly noteworthy is a case report of metastatic paraganglioma, where a nine-year-old pediatric patient achieved complete response after four cycles of treatment, highlighting the potential high efficacy of this therapy in specific populations [50]. In the context of prostate cancer, subgroup analysis of the TheraP trial revealed that 29% of patients in the [177Lu]Lu-PSMA treatment group achieved a prostate-specific antigen (PSA) response rate greater than 50%, with a 2.3-fold extension in pain relief duration compared to the control group [24]. The VISION trial also demonstrated significant improvements in key efficacy endpoints for patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA-617 in combination with standard of care. Specifically, the objective response rate was 51.0% in the [177Lu]Lu-PSMA-617 group, compared to just 3.0% in the control group. Moreover, the time to the first symptomatic skeletal event was substantially prolonged in the treatment group, with a median of 11.5 months versus 6.8 months in the control group (HR = 0.50) [51].
Additionally, several datasets demonstrate that 177Lu therapy significantly improves patient survival outcomes. The 5-year follow-up data from the NETTER-1 Phase III study showed that the median OS in the [177Lu]Lu-DOTA-TATE group reached 48 months, an 11.7-month extension compared to the control group (HR = 0.84) (Fig. 3A), with a low treatment-related incidence of myelodysplastic syndrome (1.8%), indicating a high safety profile [52]. Furthermore, the ENZA-p (ANZUP 1901) Phase II trial, presented at the 2025 ASCO-GU meeting, enrolled 162 patients with metastatic castration-resistant prostate cancer (mCRPC) (83 in the [177Lu]Lu-PSMA-617 plus enzalutamide arm and 79 in the enzalutamide alone arm). The combination therapy achieved a median OS of 34 months, compared to 26 months for enzalutamide alone (HR = 0.55, 95% CI 0.36–0.84, p = 0.0053) [53]. A multicenter study further demonstrated that patients receiving ≥ 6 cycles of [177Lu]Lu-PSMA treatment achieved a median OS of 31.3 months, representing a 42% improvement compared to the standard 4-cycle regimen, emphasizing the importance of individualized dose adjustment [54] .
Cross-sectional comparison
In horizontal comparisons of treatment regimens, 177Lu demonstrates distinct advantages.Compared to chemotherapy: The TheraP trial compared the efficacy of [177Lu]Lu-PSMA with cabazitaxel chemotherapy. The results showed that patients in the [177Lu]Lu-PSMA-617 treatment group had a higher frequency of prostate-specific antigen (PSA) decline ≥ 50% from baseline compared to those in the cabazitaxel group (66% vs. 37%) (Fig. 3B) [24]. Compared to conventional radionuclides: A randomized controlled study targeting bone metastases demonstrated that [177Lu]Lu-DOTA-IBA exhibited comparable efficacy to [153Sm] Sm-EDTMP, but with lower hematological toxicity and no observed severe nephrotoxicity, showing superior safety profile compared to traditional radiopharmaceuticals [55]. This further confirms the superiority of 177Lu in treating bone metastases.
Short-term toxicity and long-term organ effects of drugs
Radiopharmaceuticals may induce certain toxic reactions in patients during tumor treatment. The toxicity caused by 177Lu radiopharmaceuticals is primarily Radiopharmaceuticals can induce certain toxic reactions during tumor treatment, primarily due to the radiation effects of beta particles emitted by 177Lu. When beta particles penetrate tissues, their energy is deposited within the tissue, leading to DNA and biomolecular damage [6, 56]. Additionally, the distribution of the radiopharmaceutical in vivo influences toxicity. If the drug has prolonged retention in the kidneys, the radiation dose received by the kidneys increases, which in turn elevates the risk of nephrotoxicity. Patient-specific factors, such as age, underlying diseases, and renal function, also impact radiation tolerance. These toxic reactions can be classified into acute toxicity and long-term organ effects.
Short-term toxicity
Acute toxicity typically manifests within weeks following treatment, and primarily includes bone marrow suppression, nausea, and vomiting [57, 58]. 177Lu-labeled radiopharmaceuticals, such as [177Lu]Lu-PSMA, may induce acute toxicity during clinical application. Hematological toxicity, particularly bone marrow suppression, is the most commonly observed acute toxicity. This may manifest as thrombocytopenia, leukopenia, and anemia. Patients may also experience nausea, vomiting, diarrhea, and fatigue.
Long-term organ effects
Long-term organ effects are primarily observed in the kidneys and liver, potentially leading to renal impairment and hepatic dysfunction. The kidneys serve as the primary excretory pathway for 177Lu-labeled radiopharmaceuticals, making them particularly susceptible to radiation-induced injury [59, 60]. In clinical trials of [177Lu]Lu-DOTA-TATE peptide receptor radionuclide therapy, nephrotoxicity is generally mild. Long-term follow-up data show a low incidence of renal adverse events (e.g., Grade 1–4 events occurred in 3.5%, 0.6%, 0.4%, and 0.2% of patients, respectively). However, the risk of renal function decline requires ongoing monitoring. Regarding hepatic effects, although liver metastases are a common adverse prognostic factor in patients with neuroendocrine neoplasms, treatment-related hepatotoxicity is exceedingly rare (only 0.2% for Grade 1 and Grade 2). Nonetheless, the potential cumulative radiation effects on liver function over the long term warrant continued vigilance [58, 59].
Cross-sectional comparison
177Lu offers superior toxicity profile compared to other radionuclides. In comparison with 90Y, 177Lu has a more favorable safety profile due to its lower-energy beta emissions (0.5 MeV vs. 2.27 MeV) [61], shallow tissue penetration, and reduced bone marrow toxicity. Additionally, 177Lu’s gamma emissions allow for treatment monitoring, while 90Y lacks imaging capability, increasing off-target risks. Thus, 177Lu is safer, particularly for multi-cycle regimens or patients with limited bone marrow function [62].
177Lu clinical efficacy and survival benefit analysis
177Lu-labeled radioligands have demonstrated substantial value in tumor therapy (Table 1). Their therapeutic efficacy, survival benefits, and comparative advantages over other treatment modalities have been validated in multiple studies [24, 47, 48]. The following sections systematically summarize their preclinical efficacy, clinical outcomes, and comparative performance relative to other treatment strategies.
Advances in preclinical efficacy research
In recent years, 177Lu-labeled targeted radiopharmaceuticals have exhibited significant antitumor efficacy and favorable safety profiles in preclinical oncology studies. Yang et al. developed [177Lu]Lu-LuFL, a fibroblast activation protein (FAP)–targeted radioligand that demonstrated potent therapeutic efficacy in HT-1080-FAP–positive mouse models. The radioligand markedly inhibited tumor growth, and tumor volumes in the high-dose group (24.05 MBq) were significantly reduced compared with controls. Meanwhile, treated mice maintained stable body weight (0.92–1.17 fold change), and histopathological analysis showed no observable organ damage (Fig. 2A) [44]. Notably, Luna-Gutiérrez et al. developed [177Lu]Lu-DOTA-PD-L1-i, which showed promising therapeutic potential in mouse models of metastatic lung cancer. This radioligand selectively eliminated PD-L1–positive tumor cells and achieved a tumor radiation dose of 43 mGy/MBq—ten times higher than the kidney dose and fifty times higher than the liver dose (Fig. 2B). Its tumor retention time reached 346.5 h (Fig. 2C), suggesting a highly effective precision radiotherapy approach for immune-resistant tumors [45]. Advances in dual-targeting strategies have further broadened the therapeutic capabilities of 177Lu radiopharmaceuticals. Zha et al. developed [177Lu]Lu-P17-079, a dual-targeting radioligand capable of simultaneously recognizing PSMA-positive tumors and bone metastatic lesions. The radioligand achieved an uptake of 14.7% ID/g in PSMA-positive tumors, comparable to [177Lu]Lu-PSMA-617 (14.5% ID/g), and displayed an uptake of 6.52% ID/g in bone lesions—12.5-fold higher than [177Lu]Lu -617 (0.52% ID/g). This dual-targeting capability provides a more comprehensive radiotherapeutic approach for advanced prostate cancer and represents a promising candidate for next-generation radiopharmaceutical development following Pluvicto® [39].
Clinical efficacy
Clinical studies have confirmed that 177Lu-labeled radioligands exhibit distinctive response patterns in the treatment of solid tumors. For example, in the final analysis of the NETTER-1 trial, the combination of [177Lu]Lu-DOTA-TATE and long-acting octreotide yielded a median overall survival (OS) of 48.0 months in patients with advanced midgut neuroendocrine tumors (NETs), extending OS by 11.7 months compared to high-dose long-acting octreotide monotherapy (36.3 months; hazard ratio 0.84, 95% confidence interval 0.60–1.17; p = 0.30), although the difference lacked statistical significance. Long-term safety profiles were consistent with the known side effects, showing manageable hematologic toxicities and gastrointestinal symptoms, with no new safety signals. These findings underscore the clinically meaningful survival benefits and favorable tolerability of [177Lu]Lu-DOTA-TATE, confirming its potential role in this patient population [49]. The NETTER-2 Phase III clinical trial further demonstrated that patients receiving [177Lu]Lu-DOTA-TATE treatment achieved an objective response rate (ORR) of 43%, significantly higher than the control group’s 9.3% [18]. Particularly noteworthy is a case report of metastatic paraganglioma, where a nine-year-old pediatric patient achieved complete response after four cycles of treatment, highlighting the potential high efficacy of this therapy in specific populations [50]. In the context of prostate cancer, subgroup analysis of the TheraP trial revealed that 29% of patients in the [177Lu]Lu-PSMA treatment group achieved a prostate-specific antigen (PSA) response rate greater than 50%, with a 2.3-fold extension in pain relief duration compared to the control group [24]. The VISION trial also demonstrated significant improvements in key efficacy endpoints for patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA-617 in combination with standard of care. Specifically, the objective response rate was 51.0% in the [177Lu]Lu-PSMA-617 group, compared to just 3.0% in the control group. Moreover, the time to the first symptomatic skeletal event was substantially prolonged in the treatment group, with a median of 11.5 months versus 6.8 months in the control group (HR = 0.50) [51].
Additionally, several datasets demonstrate that 177Lu therapy significantly improves patient survival outcomes. The 5-year follow-up data from the NETTER-1 Phase III study showed that the median OS in the [177Lu]Lu-DOTA-TATE group reached 48 months, an 11.7-month extension compared to the control group (HR = 0.84) (Fig. 3A), with a low treatment-related incidence of myelodysplastic syndrome (1.8%), indicating a high safety profile [52]. Furthermore, the ENZA-p (ANZUP 1901) Phase II trial, presented at the 2025 ASCO-GU meeting, enrolled 162 patients with metastatic castration-resistant prostate cancer (mCRPC) (83 in the [177Lu]Lu-PSMA-617 plus enzalutamide arm and 79 in the enzalutamide alone arm). The combination therapy achieved a median OS of 34 months, compared to 26 months for enzalutamide alone (HR = 0.55, 95% CI 0.36–0.84, p = 0.0053) [53]. A multicenter study further demonstrated that patients receiving ≥ 6 cycles of [177Lu]Lu-PSMA treatment achieved a median OS of 31.3 months, representing a 42% improvement compared to the standard 4-cycle regimen, emphasizing the importance of individualized dose adjustment [54] .
Cross-sectional comparison
In horizontal comparisons of treatment regimens, 177Lu demonstrates distinct advantages.Compared to chemotherapy: The TheraP trial compared the efficacy of [177Lu]Lu-PSMA with cabazitaxel chemotherapy. The results showed that patients in the [177Lu]Lu-PSMA-617 treatment group had a higher frequency of prostate-specific antigen (PSA) decline ≥ 50% from baseline compared to those in the cabazitaxel group (66% vs. 37%) (Fig. 3B) [24]. Compared to conventional radionuclides: A randomized controlled study targeting bone metastases demonstrated that [177Lu]Lu-DOTA-IBA exhibited comparable efficacy to [153Sm] Sm-EDTMP, but with lower hematological toxicity and no observed severe nephrotoxicity, showing superior safety profile compared to traditional radiopharmaceuticals [55]. This further confirms the superiority of 177Lu in treating bone metastases.
Short-term toxicity and long-term organ effects of drugs
Radiopharmaceuticals may induce certain toxic reactions in patients during tumor treatment. The toxicity caused by 177Lu radiopharmaceuticals is primarily Radiopharmaceuticals can induce certain toxic reactions during tumor treatment, primarily due to the radiation effects of beta particles emitted by 177Lu. When beta particles penetrate tissues, their energy is deposited within the tissue, leading to DNA and biomolecular damage [6, 56]. Additionally, the distribution of the radiopharmaceutical in vivo influences toxicity. If the drug has prolonged retention in the kidneys, the radiation dose received by the kidneys increases, which in turn elevates the risk of nephrotoxicity. Patient-specific factors, such as age, underlying diseases, and renal function, also impact radiation tolerance. These toxic reactions can be classified into acute toxicity and long-term organ effects.
Short-term toxicity
Acute toxicity typically manifests within weeks following treatment, and primarily includes bone marrow suppression, nausea, and vomiting [57, 58]. 177Lu-labeled radiopharmaceuticals, such as [177Lu]Lu-PSMA, may induce acute toxicity during clinical application. Hematological toxicity, particularly bone marrow suppression, is the most commonly observed acute toxicity. This may manifest as thrombocytopenia, leukopenia, and anemia. Patients may also experience nausea, vomiting, diarrhea, and fatigue.
Long-term organ effects
Long-term organ effects are primarily observed in the kidneys and liver, potentially leading to renal impairment and hepatic dysfunction. The kidneys serve as the primary excretory pathway for 177Lu-labeled radiopharmaceuticals, making them particularly susceptible to radiation-induced injury [59, 60]. In clinical trials of [177Lu]Lu-DOTA-TATE peptide receptor radionuclide therapy, nephrotoxicity is generally mild. Long-term follow-up data show a low incidence of renal adverse events (e.g., Grade 1–4 events occurred in 3.5%, 0.6%, 0.4%, and 0.2% of patients, respectively). However, the risk of renal function decline requires ongoing monitoring. Regarding hepatic effects, although liver metastases are a common adverse prognostic factor in patients with neuroendocrine neoplasms, treatment-related hepatotoxicity is exceedingly rare (only 0.2% for Grade 1 and Grade 2). Nonetheless, the potential cumulative radiation effects on liver function over the long term warrant continued vigilance [58, 59].
Cross-sectional comparison
177Lu offers superior toxicity profile compared to other radionuclides. In comparison with 90Y, 177Lu has a more favorable safety profile due to its lower-energy beta emissions (0.5 MeV vs. 2.27 MeV) [61], shallow tissue penetration, and reduced bone marrow toxicity. Additionally, 177Lu’s gamma emissions allow for treatment monitoring, while 90Y lacks imaging capability, increasing off-target risks. Thus, 177Lu is safer, particularly for multi-cycle regimens or patients with limited bone marrow function [62].
Limitations of Lu monotherapy
Limitations of 177Lu monotherapy
Although 177Lu-labeled radioligand therapy (such as [177Lu]Lu-DOTA-TATE) demonstrates significant clinical value in the treatment of solid tumors including neuroendocrine tumors and prostate cancer, its clinical application still faces multiple challenges at both biological and physical levels (Fig. 4) [63–65]. These limitations primarily stem from tumor heterogeneity, radiation dose distribution, tumor cell DNA repair mechanisms, and tumor microenvironment resistance. The following sections will introduce these mechanisms respectively [66].
Treatment bottlenecks
Tumor heterogeneity
Tumor heterogeneity refers to the diversity of tumor cells at genetic, molecular, phenotypic, or functional levels, typically manifesting as spatial heterogeneity and temporal heterogeneity. This diversity leads to inconsistent target antigen expression levels, while the efficacy of 177Lu radiopharmaceuticals is highly dependent on sustained high expression of target antigens. Therefore, heterogeneity in antigen expression may trigger targeted escape, becoming a major obstacle limiting therapeutic efficacy [67, 68].
Spatial heterogeneity
Spatial heterogeneity manifests as significant differences in tumor cells across different regions within the same tumor, between lesions, or among patients [69]. Taking pancreatic cancer as an example, FAP is ubiquitously expressed in cancer-associated fibroblasts (CAFs), but its expression levels exhibit notable variation between different metastatic sites. When using [177Lu]Lu-FAP-2286 (targeting FAP) for treatment, preclinical SPECT imaging revealed absent FAP expression in hepatic metastases, resulting in radiation absorbed doses lower than in FAP-positive lesions (such as bone metastases)—the mean absorbed dose for bone metastases was 3.0 ± 2.7 Gy/GBq, while hepatic metastases had lower doses (0.4 Gy/GBq in one case). This result highlights the constraining effect of spatial heterogeneity on therapeutic efficacy [70].
Temporal heterogeneity
Temporal heterogeneity refers to the dynamic changes exhibited by tumor cells from the primary tumor to the metastatic stage within the same patient [69]. Paschalis et al. analyzed matched primary prostate cancer (CSPC, samples at diagnosis) and mCRPC metastatic lesion samples from 38 patients, comparing PSMA expression differences between CSPC and mCRPC stages and correlating with clinical outcomes. They found that PSMA expression exhibits significant temporal heterogeneity during disease progression: some patients showed PSMA upregulation while others maintained persistently low expression. This phenomenon impacts long-term therapeutic efficacy [71].
Radiation dose distribution
Due to tumor heterogeneity and the limited penetration depth of β-particles emitted by 177Lu in tumor tissue, dose distribution becomes uneven, which affects treatment efficacy. Taking [177Lu]Lu-lilotomab satetraxetan (targeting CD20) treatment for diffuse large B-cell lymphoma (DLBCL) as an example, during treatment, SPECT/CT imaging was performed at multiple time points to calculate tumor radioactivity concentration, and the OLINDA sphere model was used to calculate absorbed doses. Results showed dose variations both between different tumors within the same patient and at different locations within the same tumor. Uneven dose distribution directly leads to differential radiobiological effects in tumor subregions. Clinical data revealed that among DLBCL patients receiving [177Lu]Lu-lilotomab treatment, the complete response (CR) rate was only 18%, partial response (PR) rate was 22%, while patients with stable disease (SD) or progressive disease (PD) accounted for as high as 60%. In-depth analysis revealed that the proportion of residual viable tumor cells in low-dose regions (D90% <100 cGy) showed a strong positive correlation with metabolic recurrence on PET/CT at 3 months post-treatment (r = 0.74, p < 0.001). For example, among multiple lesions in Patient 19, a lymph node lesion receiving 794 cGy achieved CR, while a bone lesion receiving only 149 cGy progressed within 6 months [72, 73].
Problems of drug resistance
Despite 177Lu radiopharmaceuticals demonstrating favorable efficacy in multiple tumor treatments, drug resistance remains a major challenge in clinical therapy. Tumor cells may develop resistance to treatment through various mechanisms, including activation of DNA repair pathways and alterations in the tumor microenvironment. These resistance mechanisms limit the therapeutic effectiveness of single 177Lu radiopharmaceutical treatment in some patients. The following sections will introduce these two resistance mechanisms respectively [74–76].
Tumor cell DNA repair mechanisms
DNA repair mechanisms represent a series of complex processes evolved by cells to maintain genomic stability, designed to repair DNA damage induced by exogenous factors (such as ultraviolet radiation, chemicals) or radioactive materials (such as β-particles emitted by 177Lu). 177Lu primarily induces DNA double-strand breaks (DSBs) in tumor cells through β-ray emission, thereby triggering apoptosis or necrosis. However, tumor cells can evade this cytotoxic effect by activating multiple DNA repair pathways, with the primary DNA repair mechanisms including homologous recombination repair (HRR), non-homologous end joining (NHEJ), and others [77].
Taking HRR as an example, homologous recombination repair is an important mechanism for repairing DNA double-strand breaks, which relies on sister chromatids as templates to perform precise repair during the S/G2 phase of the cell cycle. This process is primarily regulated by BRCA1 and BRCA2 genes and involves RAD51-mediated DNA strand exchange. In patients with BRCA1/2 mutations, HRR function is impaired, and the ability of tumor cells to repair DSBs is significantly reduced, making them more sensitive to radiation damage from 177Lu [78].
The activation of DNA repair pathways reveals a key bottleneck in 177Lu monotherapy: tumor cells escape death by repairing radiation-induced DSBs. Targeting this mechanism, combination with DNA repair inhibitors (such as PARP inhibitors) [79] can block HRR or NHEJ, further amplifying the cytotoxic effects of 177Lu, providing a theoretical basis for overcoming resistance.
Tumor microenvironment resistance
The tumor microenvironment (TME) is a complex network of cells, molecules, and their interactions surrounding tumor cells. The composition of the tumor microenvironment includes tumor cells, immune cells, vasculature, fibroblasts, and other components, whose interactions play crucial roles in tumorigenesis, progression, and treatment resistance. Certain factors within the TME may lead to decreased efficacy of targeted therapy, such as hypoxic environments and immunosuppression. These factors work synergistically to confer resistance to 177Lu radiopharmaceuticals in tumor cells [80, 81].
Oxygen-deficient enviroment
Hypoxic regions within the tumor microenvironment exert inhibitory effects on radiopharmaceutical efficacy. Under hypoxic conditions, tumor cell metabolic processes undergo alterations, with lactate accumulation and pH decline (as low as 6.1) reducing ROS generation [81]. ROS represents one of the key factors inducing tumor cell death during radiotherapy; therefore, the presence of hypoxic regions significantly diminishes the therapeutic effectiveness of radiopharmaceuticals [82].
Immunosuppression
Immunosuppression within the TME is primarily driven by regulatory Tregs and immune checkpoints (such as the PD-L1/PD-1 axis). Tregs suppress CD8⁺ T cell anti-tumor activity through secretion of IL-10 and TGF-β, while PD-L1 binding to PD-1 blocks T cell proliferation, facilitating immune escape [83, 84].
For example, Liang Zhao’s team discovered in their study of [177Lu]Lu-LNC1004 (targeting FAP) that monotherapy upregulated PD-L1 expression through activation of the JAK/STAT signaling pathway, suppressed CD8⁺ T cell function, and enhanced Treg infiltration, forming a local immunosuppressive network. Single-cell sequencing (scRNA-seq) further revealed that T cell receptor (TCR) diversity decreased post-treatment, with residual tumor cells maintaining low immunogenicity through downregulation of interferon response pathways. Although 177Lu-induced DNA damage can trigger immunogenic cell death (ICD), its immune-activating effects are counteracted by PD-L1 signaling, leading to tumor escape [85].
This finding suggests that 177Lu radiopharmaceutical monotherapy may weaken long-term anti-tumor immunity due to tumor microenvironment remodeling. These immune escape mechanisms enable tumor cells to evade immune system attacks, thereby exhibiting resistance during treatment. Combination with immune checkpoint inhibitors (such as anti-PD-L1 antibodies) can reverse this resistance mechanism and enhance synergistic anti-tumor effects.
Although 177Lu-labeled radioligand therapy (such as [177Lu]Lu-DOTA-TATE) demonstrates significant clinical value in the treatment of solid tumors including neuroendocrine tumors and prostate cancer, its clinical application still faces multiple challenges at both biological and physical levels (Fig. 4) [63–65]. These limitations primarily stem from tumor heterogeneity, radiation dose distribution, tumor cell DNA repair mechanisms, and tumor microenvironment resistance. The following sections will introduce these mechanisms respectively [66].
Treatment bottlenecks
Tumor heterogeneity
Tumor heterogeneity refers to the diversity of tumor cells at genetic, molecular, phenotypic, or functional levels, typically manifesting as spatial heterogeneity and temporal heterogeneity. This diversity leads to inconsistent target antigen expression levels, while the efficacy of 177Lu radiopharmaceuticals is highly dependent on sustained high expression of target antigens. Therefore, heterogeneity in antigen expression may trigger targeted escape, becoming a major obstacle limiting therapeutic efficacy [67, 68].
Spatial heterogeneity
Spatial heterogeneity manifests as significant differences in tumor cells across different regions within the same tumor, between lesions, or among patients [69]. Taking pancreatic cancer as an example, FAP is ubiquitously expressed in cancer-associated fibroblasts (CAFs), but its expression levels exhibit notable variation between different metastatic sites. When using [177Lu]Lu-FAP-2286 (targeting FAP) for treatment, preclinical SPECT imaging revealed absent FAP expression in hepatic metastases, resulting in radiation absorbed doses lower than in FAP-positive lesions (such as bone metastases)—the mean absorbed dose for bone metastases was 3.0 ± 2.7 Gy/GBq, while hepatic metastases had lower doses (0.4 Gy/GBq in one case). This result highlights the constraining effect of spatial heterogeneity on therapeutic efficacy [70].
Temporal heterogeneity
Temporal heterogeneity refers to the dynamic changes exhibited by tumor cells from the primary tumor to the metastatic stage within the same patient [69]. Paschalis et al. analyzed matched primary prostate cancer (CSPC, samples at diagnosis) and mCRPC metastatic lesion samples from 38 patients, comparing PSMA expression differences between CSPC and mCRPC stages and correlating with clinical outcomes. They found that PSMA expression exhibits significant temporal heterogeneity during disease progression: some patients showed PSMA upregulation while others maintained persistently low expression. This phenomenon impacts long-term therapeutic efficacy [71].
Radiation dose distribution
Due to tumor heterogeneity and the limited penetration depth of β-particles emitted by 177Lu in tumor tissue, dose distribution becomes uneven, which affects treatment efficacy. Taking [177Lu]Lu-lilotomab satetraxetan (targeting CD20) treatment for diffuse large B-cell lymphoma (DLBCL) as an example, during treatment, SPECT/CT imaging was performed at multiple time points to calculate tumor radioactivity concentration, and the OLINDA sphere model was used to calculate absorbed doses. Results showed dose variations both between different tumors within the same patient and at different locations within the same tumor. Uneven dose distribution directly leads to differential radiobiological effects in tumor subregions. Clinical data revealed that among DLBCL patients receiving [177Lu]Lu-lilotomab treatment, the complete response (CR) rate was only 18%, partial response (PR) rate was 22%, while patients with stable disease (SD) or progressive disease (PD) accounted for as high as 60%. In-depth analysis revealed that the proportion of residual viable tumor cells in low-dose regions (D90% <100 cGy) showed a strong positive correlation with metabolic recurrence on PET/CT at 3 months post-treatment (r = 0.74, p < 0.001). For example, among multiple lesions in Patient 19, a lymph node lesion receiving 794 cGy achieved CR, while a bone lesion receiving only 149 cGy progressed within 6 months [72, 73].
Problems of drug resistance
Despite 177Lu radiopharmaceuticals demonstrating favorable efficacy in multiple tumor treatments, drug resistance remains a major challenge in clinical therapy. Tumor cells may develop resistance to treatment through various mechanisms, including activation of DNA repair pathways and alterations in the tumor microenvironment. These resistance mechanisms limit the therapeutic effectiveness of single 177Lu radiopharmaceutical treatment in some patients. The following sections will introduce these two resistance mechanisms respectively [74–76].
Tumor cell DNA repair mechanisms
DNA repair mechanisms represent a series of complex processes evolved by cells to maintain genomic stability, designed to repair DNA damage induced by exogenous factors (such as ultraviolet radiation, chemicals) or radioactive materials (such as β-particles emitted by 177Lu). 177Lu primarily induces DNA double-strand breaks (DSBs) in tumor cells through β-ray emission, thereby triggering apoptosis or necrosis. However, tumor cells can evade this cytotoxic effect by activating multiple DNA repair pathways, with the primary DNA repair mechanisms including homologous recombination repair (HRR), non-homologous end joining (NHEJ), and others [77].
Taking HRR as an example, homologous recombination repair is an important mechanism for repairing DNA double-strand breaks, which relies on sister chromatids as templates to perform precise repair during the S/G2 phase of the cell cycle. This process is primarily regulated by BRCA1 and BRCA2 genes and involves RAD51-mediated DNA strand exchange. In patients with BRCA1/2 mutations, HRR function is impaired, and the ability of tumor cells to repair DSBs is significantly reduced, making them more sensitive to radiation damage from 177Lu [78].
The activation of DNA repair pathways reveals a key bottleneck in 177Lu monotherapy: tumor cells escape death by repairing radiation-induced DSBs. Targeting this mechanism, combination with DNA repair inhibitors (such as PARP inhibitors) [79] can block HRR or NHEJ, further amplifying the cytotoxic effects of 177Lu, providing a theoretical basis for overcoming resistance.
Tumor microenvironment resistance
The tumor microenvironment (TME) is a complex network of cells, molecules, and their interactions surrounding tumor cells. The composition of the tumor microenvironment includes tumor cells, immune cells, vasculature, fibroblasts, and other components, whose interactions play crucial roles in tumorigenesis, progression, and treatment resistance. Certain factors within the TME may lead to decreased efficacy of targeted therapy, such as hypoxic environments and immunosuppression. These factors work synergistically to confer resistance to 177Lu radiopharmaceuticals in tumor cells [80, 81].
Oxygen-deficient enviroment
Hypoxic regions within the tumor microenvironment exert inhibitory effects on radiopharmaceutical efficacy. Under hypoxic conditions, tumor cell metabolic processes undergo alterations, with lactate accumulation and pH decline (as low as 6.1) reducing ROS generation [81]. ROS represents one of the key factors inducing tumor cell death during radiotherapy; therefore, the presence of hypoxic regions significantly diminishes the therapeutic effectiveness of radiopharmaceuticals [82].
Immunosuppression
Immunosuppression within the TME is primarily driven by regulatory Tregs and immune checkpoints (such as the PD-L1/PD-1 axis). Tregs suppress CD8⁺ T cell anti-tumor activity through secretion of IL-10 and TGF-β, while PD-L1 binding to PD-1 blocks T cell proliferation, facilitating immune escape [83, 84].
For example, Liang Zhao’s team discovered in their study of [177Lu]Lu-LNC1004 (targeting FAP) that monotherapy upregulated PD-L1 expression through activation of the JAK/STAT signaling pathway, suppressed CD8⁺ T cell function, and enhanced Treg infiltration, forming a local immunosuppressive network. Single-cell sequencing (scRNA-seq) further revealed that T cell receptor (TCR) diversity decreased post-treatment, with residual tumor cells maintaining low immunogenicity through downregulation of interferon response pathways. Although 177Lu-induced DNA damage can trigger immunogenic cell death (ICD), its immune-activating effects are counteracted by PD-L1 signaling, leading to tumor escape [85].
This finding suggests that 177Lu radiopharmaceutical monotherapy may weaken long-term anti-tumor immunity due to tumor microenvironment remodeling. These immune escape mechanisms enable tumor cells to evade immune system attacks, thereby exhibiting resistance during treatment. Combination with immune checkpoint inhibitors (such as anti-PD-L1 antibodies) can reverse this resistance mechanism and enhance synergistic anti-tumor effects.
Current status and advances in combination therapy strategies
Current status and advances in combination therapy strategies
In tumor treatment, monotherapy often fails to achieve durable remission due to limitations imposed by tumor heterogeneity, acquired resistance, and toxicity constraints. Combination therapy strategies based on multi-mechanism synergy, through spatiotemporal integration of drugs or therapeutic modalities with different mechanisms of action, can overcome the limitations of single-agent treatment while optimizing clinical benefits through enhanced efficacy and reduced toxicity. Currently, 177Lu radiopharmaceutical combination therapy has achieved research progress in multiple cancer fields (Table 2), including combination with chemotherapy, immunotherapy, and targeted drug therapy.
Synergy with chemotherapy
Mechanism of action of the combination of 177Lu and chemotherapy
Chemotherapy represents one of the cornerstones of tumor treatment, primarily achieving tumor cell cytotoxicity through the use of cytotoxic drugs that interfere with cellular DNA replication, transcription, or cell division processes. Common chemotherapy agents include platinum compounds (such as cisplatin, carboplatin) and taxanes (such as paclitaxel, docetaxel), which play crucial roles in tumor therapy [107–109]. When 177Lu is combined with chemotherapy agents, synergistic enhancement mechanisms may be generated. Specifically, this synergistic effect may manifest in the following three aspects:
DNA damage synergistic effects
Chemotherapy drugs (such as platinum compounds) induce single-strand or double-strand breaks through formation of DNA adducts or cross-links, while β-particles emitted by 177Lu cause DNA double-strand breaks (DSBs) through direct ionization or indirect generation of reactive oxygen species (ROS). When applied in combination, the DNA damage from both modalities accumulates at the molecular level, exceeding the repair threshold of tumor cells (typically 10–15 DSB/cell), significantly enhancing cytotoxic effects [110];
Cell cycle regulation alterations
Certain chemotherapy drugs can modulate cell cycle progression, enriching tumor cells in the radiation-sensitive G2/M phase. For example, paclitaxel arrests cells in the G2/M phase by stabilizing microtubule proteins, during which chromatin is highly condensed and the efficiency of radiation-induced DSB repair decreases by approximately 30%, providing a more effective cytotoxic window for 177Lu β-particles [107].
Complementary killing at different stages
Chemotherapy drugs can rapidly eliminate proliferating tumor cells (peak effect typically within 24–48 h), while 177Lu exerts long-term control over low-proliferating or drug-resistant residual cells through sustained β-ray emission (half-life 6.65 days). This temporal complementarity significantly enhances treatment thoroughness and reduces recurrence risk [68].
Examples of combination therapy
Multiple clinical studies have confirmed the synergistic effects of 177Lu radiopharmaceuticals combined with chemotherapy. In the field of neuroendocrine tumors, Adnan et al. reported the first case of a patient with well-differentiated recurrent sinonasal neuroendocrine carcinoma receiving [177Lu]Lu-DOTA-TATE combined with carboplatin/etoposide treatment [110]. Three months post-treatment, the primary lesion volume decreased by 73% (7.0 × 4.6 × 5.0 cm→1.9 × 0.8 cm), right hilar lymph nodes completely regressed, and subsequent [68Ga]Ga-DOTA-TATE PET/CT imaging showed SUVmax reduction from baseline 10.6 to 5.53 (Fig. 5A). This result not only validated the feasibility of sequential application of platinum-based chemotherapy with peptide receptor radionuclide therapy (PRRT), but also demonstrated significant advantages of the combination regimen in terms of tolerability and symptom relief. In prostate cancer treatment, Kinikoglu et al.‘s retrospective study (n = 104) found that [111] [177Lu]Lu-PSMA-617 combined with androgen receptor pathway inhibitors (ARPIs) significantly prolonged median progression-free survival compared to monotherapy (11 vs. 5.6 months, HR = 0.47, p < 0.01), with OS showing an improving trend (20.3 vs. 15.9 months, p = 0.06). Notably, 94.1% of patients in the combination group had previously received ARPI treatment, suggesting this regimen retains clinical value for drug-resistant patients.
Furthermore, in terms of innovative combination strategies, Timin et al. developed a calcium carbonate nanocarrier simultaneously loading cisplatin and 177Lu, demonstrating synergistic effects in a CT26 lung metastasis model: the 177Lu monotherapy group showed 50 ± 7 metastatic nodules, cisplatin group 65 ± 10, while the combination group decreased to 37 ± 5 (p < 0.05) [101]. Cytryniak et al. constructed lipid nanoparticles capable of simultaneously loading doxorubicin and DOTAGA-177Lu complexes, with in vitro experiments showing the combination group achieved 40% higher cytotoxicity against HeLa cells compared to monotherapy groups, confirming the technical advantages of nanocarriers in synergistic drug delivery [102].
Combination with immunotherapy
Synergistic effects of combined 177Lu with immunotherapy
Immunotherapy, particularly immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) and CAR-T cell therapy, has become an important modality in tumor treatment. Immune checkpoint inhibitors activate the anti-tumor activity of the immune system by blocking inhibitory receptors on immune cells, thereby relieving immunosuppression. CAR-T cell therapy involves genetically engineering patient T cells to express receptors that recognize tumor cells, thus enhancing T cell cytotoxic capacity [112, 113].
The combination of 177Lu with immunotherapy may generate synergistic effects, with primary mechanisms including [114, 115]:
Radiation-induced ICD
177Lu radiation kills tumor cells, causing them to undergo ICD. ICD represents a specialized form of cell death that releases tumor antigens and inflammatory factors, activating the body’s anti-tumor immune response. For example, Zhao et al. demonstrated significant synergistic anti-tumor effects through [177Lu]Lu-LNC1004 (targeting FAP) combined with anti-PD-L1 immune checkpoint blockade therapy in animal models and in vitro experiments: [177Lu]Lu-LNC1004 kills tumor cells, releasing antigens and upregulating PD-L1, while immune checkpoint inhibitors relieve T cell suppression. Together, they synergistically remodel the immunosuppressive microenvironment, promoting the anti-tumor activity of CD8 + T cells, M1 macrophages, and IRF1 + neutrophils [85].
Enhance immune activity in the tumor microenvironment. 177Lu can modify the tumor microenvironment to favor immune cell infiltration and activation. For example, 177Lu can promote tumor vascular normalization, improving oxygen supply to tumor tissues, thereby enhancing immune cell activity [80].
Examples of combination therapy
The combination of 177Lu radiopharmaceuticals with immunotherapy has achieved phased results across multiple cancer types. In the field of neuroendocrine tumors, a phase I clinical trial of [177Lu]Lu-DOTA-TATE combined with nivolumab showed an ORR of 14.3% and disease control rate of 42.9% in patients with pulmonary neuroendocrine tumors, with atypical carcinoid patients achieving a median PFS of 6 months. In patients who achieved partial remission (study ID # 2), [68Ga]Ga-DOTA-TATE PET scans showed that the combined therapy significantly reduced target lesions (Fig. 5B) [91]. These data indicate that combination therapy exhibits clinical activity in some patients. Ferdinandus et al.‘s study further confirmed that [177Lu]Lu-DOTAT-OC combined with ipilimumab/nivolumab enabled patients with metastatic neuroendocrine tumors who failed multiple lines of therapy to achieve sustained remission for 5 months, with bone metastases volume reduction > 50%. Treatment-related adverse events were primarily hematological toxicity (grade 3 leukopenia incidence 11.1%) and mild thyroiditis, with no unexpected organ toxicity [116].
In solid tumor research, Chen et al. found that in microsatellite stable colorectal cancer (MSS-CRC) models, 177Lu labeled FAP dimer probe ([177Lu]Lu-DOTA-2P(FAPI)2) induced tumor cell DNA double-strand breaks and upregulated PD-L1 expression. Combined with anti-PD-L1 monoclonal antibody treatment, the complete response rate reached 100%, and cured mice developed long-term immune memory against tumor rechallenge. Single-cell sequencing analysis revealed that this combination regimen enhanced T cell-tumor cell interactions through activation of the FASL-Fas pathway, promoting a 2.3-fold increase in CD8⁺ T cell infiltration while increasing mature neutrophil proportion by 40% and decreasing regulatory T cell (Treg) proportion by 28%, significantly remodeling the immunosuppressive microenvironment [117]. In breast cancer, Guzik et al. found that [177Lu]Lu-DOTA-folate (3.5 Gy) combined with anti-CTLA-4 treatment achieved survival > 70 days (compared to 12 days in controls). This effect may be closely related to PD-L1 mRNA upregulation and decreased Treg cell proportions [104].
The combination of 177Lu radiopharmaceuticals with immunotherapy achieves significant synergistic anti-tumor effects through ICD induction and TME remodeling. Clinical and experimental data demonstrate that this strategy shows potential across various cancers including neuroendocrine tumors, colorectal cancer, and breast cancer, with particularly breakthrough significance in drug-resistant tumors. However, current research still requires further expansion of sample sizes and optimization of combination regimens to validate long-term efficacy and safety. This direction opens new prospects for clinical applications of 177Lu and merits in-depth exploration.
Exploration of combinations with external radiotherapy, targeted drugs and other treatment modalities
Synergy with external radiotherapy: systemic-local synergy and radiosensitization effect
External beam radiation therapy (EBRT) combined with 177Lu radiopharmaceuticals demonstrates significant synergistic enhancement in prostate cancer treatment. Research by Arbuznikova et al. indicates that [177Lu]Lu-PSMA-617 combined with EBRT treatment for prostate cancer exhibits significant multiple advantages [118]: Specifically, EBRT targets primary lesions or oligometastatic sites through high-dose ablation (such as 54 Gy fractionated irradiation), effectively controlling local disease; while [177Lu]Lu-PSMA-617 specifically binds to tumor cells expressing prostate-specific membrane antigen (PSMA), eliminating occult micrometastases and achieving systemic therapeutic coverage. This complementary strategy has been validated in clinical cases: a patient with locally advanced prostate cancer achieved 5-year biochemical recurrence-free survival (no PSA elevation) after receiving EBRT combined with 3 cycles of [177Lu]Lu-PSMA-617 (total dose 14.9GBq). This result not only highlights the synergistic effects of combination therapy in local control and systemic clearance, but also provides strong clinical evidence for prolonging PFS.
Mechanistically, high-dose EBRT irradiation can induce local tumor cell apoptosis and disrupt the tumor microenvironment, while β-particles from [177Lu]Lu-PSMA-617 precisely target distant micrometastases through PSMA receptor binding, creating spatiotemporal therapeutic complementarity. EBRT not only directly kills tumor cells but can also enhance subsequent [177Lu]Lu-PSMA-617 efficacy by upregulating PSMA expression. Studies found that 4 h after EBRT irradiation, PSMA mRNA levels in tumor cells increased by 2.6-fold, with this transient gene expression upregulation creating favorable conditions for radioligand uptake. Mechanistically, radiation-induced DNA damage and stress responses may activate PSMA transcription factors (such as NF-κB), thereby increasing target density and enhancing [177Lu]Lu-PSMA-617 accumulation and cytotoxic effects in tumor tissues. This discovery of radiosensitization effects aligns with theories of radiation-induced gene expression changes, providing scientific basis for the temporal design of combination therapy.
Combined targeted therapy and other experimental treatment options
Combined targeted therapy
Recent studies have demonstrated that the combination of 177Lu radiopharmaceuticals with targeted drugs (such as PARP inhibitors and mTOR inhibitors) can enhance antitumor efficacy through synergistic effects. For instance, there exists a significant synthetic lethal effect between β-radiation-induced DNA single-strand breaks (SSB) and the base excision repair (BER) pathway blocked by PARP inhibitors. In pancreatic neuroendocrine tumor models, combination therapy with PARP inhibitor Fluzoparib and [177Lu]Lu-DOTATATE increased cell proliferation inhibition rates from 35.6% to 16.6% in monotherapy groups to 73.2%. In-depth mechanistic studies revealed that β-radiation released by 177Lu generates ROS through ionization, causing DNA strand breaks in tumor cells, while Fluzoparib inhibits PARP1/2 enzyme activity, blocking BER pathway repair of radiation damage and simultaneously inducing replication fork stalling and replication stress, ultimately leading to cell cycle arrest at G2/M phase and triggering apoptotic cascades [119]; Furthermore, research by Rauch et al. revealed that combination treatment with Olaparib and [177Lu]Lu-DOTATATE reduced clonogenic survival rates of small cell lung cancer cells by 67-fold (Fig. 5C). The mechanism involves Olaparib’s inhibition of HRR key proteins BRCA1/2, preventing effective repair of β-radiation-induced double-strand breaks (DSB), thereby achieving radiosensitization effects [120]. In clinical studies combining [177Lu]Lu-PSMA-617 with Olaparib for treating mCRPC, patients receiving combination therapy achieved PSA50 and PSA90 response rates of 62% and 48%, respectively, with no unpredictable toxicity [121], demonstrating the feasibility of this combination strategy. Additionally, radiation emitted by 177Lu may influence the tumor microenvironment—by disrupting tumor architecture and vascular systems, it increases drug permeability, thereby providing a " permeability window” for targeted carriers [122, 123]. Therefore, future research should compare the accumulation of targeted drugs in tumor centers between monotherapy and combination therapy to determine this potential synergistic mechanism.
Hyperthermia synergy
Emerging research has explored the combined potential of hyperthermia with radioisotope therapy. Semiconducting polymer nanoparticles (such as [177Lu]Lu-SPN-GIP) combined with near-infrared photothermal therapy (PTT) significantly increase vascular permeability and blood perfusion by elevating local tumor temperature to 45℃. In in vivo experiments, the combination therapy group achieved complete tumor ablation within 21 days, significantly outperforming monotherapy (both RT and PTT groups showed residual tumors) [105]. The mechanisms of hyperthermia include: thermal stress-induced tumor cell apoptosis, enhancing the cytotoxic effects of radioisotopes; improvement of the tumor microenvironment (such as alleviating hypoxia), optimizing drug distribution. This combined strategy not only enhances therapeutic efficacy but also provides new insights for reducing toxicity.
Nanocarrier enhancement
The introduction of nanotechnology has further expanded the possibilities for combination therapy. Gold nanoparticles (diameter 10 nm) combined with [177Lu]Lu-DOTA-TATE can enhance gamma ray energy deposition in tumor tissue through the photoelectric effect, significantly increase the apoptosis rate of hepatocellular carcinoma cells compared to the monotherapy group [106]. The physical basis of this effect lies in the high atomic number of gold nanoparticles (Z = 79), which increases the photon-matter interaction cross-section, thereby amplifying the local radiation dose. Biologically, the enhanced radiation effect leads to a significant increase in DNA double-strand breaks, further improving therapeutic efficacy. Meanwhile, Salvanou et al. developed the MAPAD system by integrating 177Lu with functionalized iron oxide nanoparticles (IONs) and covalently conjugating the chemotherapeutic agent doxorubicin (DOX) and the targeting antibody bevacizumab (BVCZ). This multifunctional platform markedly enhanced the efficacy of targeted radiotherapy and exhibited outstanding antitumor activity. In a 4T1 triple-negative breast cancer mouse model, a single intratumoral injection of [177Lu]Lu-MAPAD (5 MBq) elicited a robust therapeutic response. Tumor growth in the treated mice was substantially inhibited, and their survival was prolonged to 50 days, whereas all control animals were euthanized within 17 days due to excessive tumor burden [124].
In tumor treatment, monotherapy often fails to achieve durable remission due to limitations imposed by tumor heterogeneity, acquired resistance, and toxicity constraints. Combination therapy strategies based on multi-mechanism synergy, through spatiotemporal integration of drugs or therapeutic modalities with different mechanisms of action, can overcome the limitations of single-agent treatment while optimizing clinical benefits through enhanced efficacy and reduced toxicity. Currently, 177Lu radiopharmaceutical combination therapy has achieved research progress in multiple cancer fields (Table 2), including combination with chemotherapy, immunotherapy, and targeted drug therapy.
Synergy with chemotherapy
Mechanism of action of the combination of 177Lu and chemotherapy
Chemotherapy represents one of the cornerstones of tumor treatment, primarily achieving tumor cell cytotoxicity through the use of cytotoxic drugs that interfere with cellular DNA replication, transcription, or cell division processes. Common chemotherapy agents include platinum compounds (such as cisplatin, carboplatin) and taxanes (such as paclitaxel, docetaxel), which play crucial roles in tumor therapy [107–109]. When 177Lu is combined with chemotherapy agents, synergistic enhancement mechanisms may be generated. Specifically, this synergistic effect may manifest in the following three aspects:
DNA damage synergistic effects
Chemotherapy drugs (such as platinum compounds) induce single-strand or double-strand breaks through formation of DNA adducts or cross-links, while β-particles emitted by 177Lu cause DNA double-strand breaks (DSBs) through direct ionization or indirect generation of reactive oxygen species (ROS). When applied in combination, the DNA damage from both modalities accumulates at the molecular level, exceeding the repair threshold of tumor cells (typically 10–15 DSB/cell), significantly enhancing cytotoxic effects [110];
Cell cycle regulation alterations
Certain chemotherapy drugs can modulate cell cycle progression, enriching tumor cells in the radiation-sensitive G2/M phase. For example, paclitaxel arrests cells in the G2/M phase by stabilizing microtubule proteins, during which chromatin is highly condensed and the efficiency of radiation-induced DSB repair decreases by approximately 30%, providing a more effective cytotoxic window for 177Lu β-particles [107].
Complementary killing at different stages
Chemotherapy drugs can rapidly eliminate proliferating tumor cells (peak effect typically within 24–48 h), while 177Lu exerts long-term control over low-proliferating or drug-resistant residual cells through sustained β-ray emission (half-life 6.65 days). This temporal complementarity significantly enhances treatment thoroughness and reduces recurrence risk [68].
Examples of combination therapy
Multiple clinical studies have confirmed the synergistic effects of 177Lu radiopharmaceuticals combined with chemotherapy. In the field of neuroendocrine tumors, Adnan et al. reported the first case of a patient with well-differentiated recurrent sinonasal neuroendocrine carcinoma receiving [177Lu]Lu-DOTA-TATE combined with carboplatin/etoposide treatment [110]. Three months post-treatment, the primary lesion volume decreased by 73% (7.0 × 4.6 × 5.0 cm→1.9 × 0.8 cm), right hilar lymph nodes completely regressed, and subsequent [68Ga]Ga-DOTA-TATE PET/CT imaging showed SUVmax reduction from baseline 10.6 to 5.53 (Fig. 5A). This result not only validated the feasibility of sequential application of platinum-based chemotherapy with peptide receptor radionuclide therapy (PRRT), but also demonstrated significant advantages of the combination regimen in terms of tolerability and symptom relief. In prostate cancer treatment, Kinikoglu et al.‘s retrospective study (n = 104) found that [111] [177Lu]Lu-PSMA-617 combined with androgen receptor pathway inhibitors (ARPIs) significantly prolonged median progression-free survival compared to monotherapy (11 vs. 5.6 months, HR = 0.47, p < 0.01), with OS showing an improving trend (20.3 vs. 15.9 months, p = 0.06). Notably, 94.1% of patients in the combination group had previously received ARPI treatment, suggesting this regimen retains clinical value for drug-resistant patients.
Furthermore, in terms of innovative combination strategies, Timin et al. developed a calcium carbonate nanocarrier simultaneously loading cisplatin and 177Lu, demonstrating synergistic effects in a CT26 lung metastasis model: the 177Lu monotherapy group showed 50 ± 7 metastatic nodules, cisplatin group 65 ± 10, while the combination group decreased to 37 ± 5 (p < 0.05) [101]. Cytryniak et al. constructed lipid nanoparticles capable of simultaneously loading doxorubicin and DOTAGA-177Lu complexes, with in vitro experiments showing the combination group achieved 40% higher cytotoxicity against HeLa cells compared to monotherapy groups, confirming the technical advantages of nanocarriers in synergistic drug delivery [102].
Combination with immunotherapy
Synergistic effects of combined 177Lu with immunotherapy
Immunotherapy, particularly immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) and CAR-T cell therapy, has become an important modality in tumor treatment. Immune checkpoint inhibitors activate the anti-tumor activity of the immune system by blocking inhibitory receptors on immune cells, thereby relieving immunosuppression. CAR-T cell therapy involves genetically engineering patient T cells to express receptors that recognize tumor cells, thus enhancing T cell cytotoxic capacity [112, 113].
The combination of 177Lu with immunotherapy may generate synergistic effects, with primary mechanisms including [114, 115]:
Radiation-induced ICD
177Lu radiation kills tumor cells, causing them to undergo ICD. ICD represents a specialized form of cell death that releases tumor antigens and inflammatory factors, activating the body’s anti-tumor immune response. For example, Zhao et al. demonstrated significant synergistic anti-tumor effects through [177Lu]Lu-LNC1004 (targeting FAP) combined with anti-PD-L1 immune checkpoint blockade therapy in animal models and in vitro experiments: [177Lu]Lu-LNC1004 kills tumor cells, releasing antigens and upregulating PD-L1, while immune checkpoint inhibitors relieve T cell suppression. Together, they synergistically remodel the immunosuppressive microenvironment, promoting the anti-tumor activity of CD8 + T cells, M1 macrophages, and IRF1 + neutrophils [85].
Enhance immune activity in the tumor microenvironment. 177Lu can modify the tumor microenvironment to favor immune cell infiltration and activation. For example, 177Lu can promote tumor vascular normalization, improving oxygen supply to tumor tissues, thereby enhancing immune cell activity [80].
Examples of combination therapy
The combination of 177Lu radiopharmaceuticals with immunotherapy has achieved phased results across multiple cancer types. In the field of neuroendocrine tumors, a phase I clinical trial of [177Lu]Lu-DOTA-TATE combined with nivolumab showed an ORR of 14.3% and disease control rate of 42.9% in patients with pulmonary neuroendocrine tumors, with atypical carcinoid patients achieving a median PFS of 6 months. In patients who achieved partial remission (study ID # 2), [68Ga]Ga-DOTA-TATE PET scans showed that the combined therapy significantly reduced target lesions (Fig. 5B) [91]. These data indicate that combination therapy exhibits clinical activity in some patients. Ferdinandus et al.‘s study further confirmed that [177Lu]Lu-DOTAT-OC combined with ipilimumab/nivolumab enabled patients with metastatic neuroendocrine tumors who failed multiple lines of therapy to achieve sustained remission for 5 months, with bone metastases volume reduction > 50%. Treatment-related adverse events were primarily hematological toxicity (grade 3 leukopenia incidence 11.1%) and mild thyroiditis, with no unexpected organ toxicity [116].
In solid tumor research, Chen et al. found that in microsatellite stable colorectal cancer (MSS-CRC) models, 177Lu labeled FAP dimer probe ([177Lu]Lu-DOTA-2P(FAPI)2) induced tumor cell DNA double-strand breaks and upregulated PD-L1 expression. Combined with anti-PD-L1 monoclonal antibody treatment, the complete response rate reached 100%, and cured mice developed long-term immune memory against tumor rechallenge. Single-cell sequencing analysis revealed that this combination regimen enhanced T cell-tumor cell interactions through activation of the FASL-Fas pathway, promoting a 2.3-fold increase in CD8⁺ T cell infiltration while increasing mature neutrophil proportion by 40% and decreasing regulatory T cell (Treg) proportion by 28%, significantly remodeling the immunosuppressive microenvironment [117]. In breast cancer, Guzik et al. found that [177Lu]Lu-DOTA-folate (3.5 Gy) combined with anti-CTLA-4 treatment achieved survival > 70 days (compared to 12 days in controls). This effect may be closely related to PD-L1 mRNA upregulation and decreased Treg cell proportions [104].
The combination of 177Lu radiopharmaceuticals with immunotherapy achieves significant synergistic anti-tumor effects through ICD induction and TME remodeling. Clinical and experimental data demonstrate that this strategy shows potential across various cancers including neuroendocrine tumors, colorectal cancer, and breast cancer, with particularly breakthrough significance in drug-resistant tumors. However, current research still requires further expansion of sample sizes and optimization of combination regimens to validate long-term efficacy and safety. This direction opens new prospects for clinical applications of 177Lu and merits in-depth exploration.
Exploration of combinations with external radiotherapy, targeted drugs and other treatment modalities
Synergy with external radiotherapy: systemic-local synergy and radiosensitization effect
External beam radiation therapy (EBRT) combined with 177Lu radiopharmaceuticals demonstrates significant synergistic enhancement in prostate cancer treatment. Research by Arbuznikova et al. indicates that [177Lu]Lu-PSMA-617 combined with EBRT treatment for prostate cancer exhibits significant multiple advantages [118]: Specifically, EBRT targets primary lesions or oligometastatic sites through high-dose ablation (such as 54 Gy fractionated irradiation), effectively controlling local disease; while [177Lu]Lu-PSMA-617 specifically binds to tumor cells expressing prostate-specific membrane antigen (PSMA), eliminating occult micrometastases and achieving systemic therapeutic coverage. This complementary strategy has been validated in clinical cases: a patient with locally advanced prostate cancer achieved 5-year biochemical recurrence-free survival (no PSA elevation) after receiving EBRT combined with 3 cycles of [177Lu]Lu-PSMA-617 (total dose 14.9GBq). This result not only highlights the synergistic effects of combination therapy in local control and systemic clearance, but also provides strong clinical evidence for prolonging PFS.
Mechanistically, high-dose EBRT irradiation can induce local tumor cell apoptosis and disrupt the tumor microenvironment, while β-particles from [177Lu]Lu-PSMA-617 precisely target distant micrometastases through PSMA receptor binding, creating spatiotemporal therapeutic complementarity. EBRT not only directly kills tumor cells but can also enhance subsequent [177Lu]Lu-PSMA-617 efficacy by upregulating PSMA expression. Studies found that 4 h after EBRT irradiation, PSMA mRNA levels in tumor cells increased by 2.6-fold, with this transient gene expression upregulation creating favorable conditions for radioligand uptake. Mechanistically, radiation-induced DNA damage and stress responses may activate PSMA transcription factors (such as NF-κB), thereby increasing target density and enhancing [177Lu]Lu-PSMA-617 accumulation and cytotoxic effects in tumor tissues. This discovery of radiosensitization effects aligns with theories of radiation-induced gene expression changes, providing scientific basis for the temporal design of combination therapy.
Combined targeted therapy and other experimental treatment options
Combined targeted therapy
Recent studies have demonstrated that the combination of 177Lu radiopharmaceuticals with targeted drugs (such as PARP inhibitors and mTOR inhibitors) can enhance antitumor efficacy through synergistic effects. For instance, there exists a significant synthetic lethal effect between β-radiation-induced DNA single-strand breaks (SSB) and the base excision repair (BER) pathway blocked by PARP inhibitors. In pancreatic neuroendocrine tumor models, combination therapy with PARP inhibitor Fluzoparib and [177Lu]Lu-DOTATATE increased cell proliferation inhibition rates from 35.6% to 16.6% in monotherapy groups to 73.2%. In-depth mechanistic studies revealed that β-radiation released by 177Lu generates ROS through ionization, causing DNA strand breaks in tumor cells, while Fluzoparib inhibits PARP1/2 enzyme activity, blocking BER pathway repair of radiation damage and simultaneously inducing replication fork stalling and replication stress, ultimately leading to cell cycle arrest at G2/M phase and triggering apoptotic cascades [119]; Furthermore, research by Rauch et al. revealed that combination treatment with Olaparib and [177Lu]Lu-DOTATATE reduced clonogenic survival rates of small cell lung cancer cells by 67-fold (Fig. 5C). The mechanism involves Olaparib’s inhibition of HRR key proteins BRCA1/2, preventing effective repair of β-radiation-induced double-strand breaks (DSB), thereby achieving radiosensitization effects [120]. In clinical studies combining [177Lu]Lu-PSMA-617 with Olaparib for treating mCRPC, patients receiving combination therapy achieved PSA50 and PSA90 response rates of 62% and 48%, respectively, with no unpredictable toxicity [121], demonstrating the feasibility of this combination strategy. Additionally, radiation emitted by 177Lu may influence the tumor microenvironment—by disrupting tumor architecture and vascular systems, it increases drug permeability, thereby providing a " permeability window” for targeted carriers [122, 123]. Therefore, future research should compare the accumulation of targeted drugs in tumor centers between monotherapy and combination therapy to determine this potential synergistic mechanism.
Hyperthermia synergy
Emerging research has explored the combined potential of hyperthermia with radioisotope therapy. Semiconducting polymer nanoparticles (such as [177Lu]Lu-SPN-GIP) combined with near-infrared photothermal therapy (PTT) significantly increase vascular permeability and blood perfusion by elevating local tumor temperature to 45℃. In in vivo experiments, the combination therapy group achieved complete tumor ablation within 21 days, significantly outperforming monotherapy (both RT and PTT groups showed residual tumors) [105]. The mechanisms of hyperthermia include: thermal stress-induced tumor cell apoptosis, enhancing the cytotoxic effects of radioisotopes; improvement of the tumor microenvironment (such as alleviating hypoxia), optimizing drug distribution. This combined strategy not only enhances therapeutic efficacy but also provides new insights for reducing toxicity.
Nanocarrier enhancement
The introduction of nanotechnology has further expanded the possibilities for combination therapy. Gold nanoparticles (diameter 10 nm) combined with [177Lu]Lu-DOTA-TATE can enhance gamma ray energy deposition in tumor tissue through the photoelectric effect, significantly increase the apoptosis rate of hepatocellular carcinoma cells compared to the monotherapy group [106]. The physical basis of this effect lies in the high atomic number of gold nanoparticles (Z = 79), which increases the photon-matter interaction cross-section, thereby amplifying the local radiation dose. Biologically, the enhanced radiation effect leads to a significant increase in DNA double-strand breaks, further improving therapeutic efficacy. Meanwhile, Salvanou et al. developed the MAPAD system by integrating 177Lu with functionalized iron oxide nanoparticles (IONs) and covalently conjugating the chemotherapeutic agent doxorubicin (DOX) and the targeting antibody bevacizumab (BVCZ). This multifunctional platform markedly enhanced the efficacy of targeted radiotherapy and exhibited outstanding antitumor activity. In a 4T1 triple-negative breast cancer mouse model, a single intratumoral injection of [177Lu]Lu-MAPAD (5 MBq) elicited a robust therapeutic response. Tumor growth in the treated mice was substantially inhibited, and their survival was prolonged to 50 days, whereas all control animals were euthanized within 17 days due to excessive tumor burden [124].
Challenges and directions for optimization of combination therapy
Challenges and directions for optimization of combination therapy
Combining 177Lu radiopharmaceuticals with chemotherapy and immunotherapy demonstrates significant synergistic effects in advanced cancers, including mCRPC and neuroendocrine tumors. However, this strategy presents challenges including cumulative toxicity, sequence dependency, and individual variability. This analysis examines core challenges and proposes optimization recommendations for toxicity management, temporal effects, and biomarker-guided approaches [125, 126].
Toxicity management
Combination therapy enhances efficacy through synergistic mechanisms but increases toxicity due to overlapping mechanisms [127]. The AlphaBet trial protocol highlights that the combination of 223Ra and [177Lu]Lu-PSMA-I&T in metastatic castration-resistant prostate cancer may exhibit higher hematologic toxicity compared to monotherapy: up to 13% anemia (grade 3 or higher in 8–13%) and 7% neutropenia (grade 3 or higher in 2.5–7%) versus lower rates in single-agent controls; thrombocytopenia could rise to 13% (grade 3 or higher in 6–8%) relative to 1–6% in controls, driven by overlapping myeloid suppression mechanisms [128].
Optimization strategies include Optimization strategies include Claringbold’s CAPTEM regimen. The CAPTEM regimen refers to an oral chemotherapy combination of capecitabine and temozolomide. In the literature by Claringbold et al., it was designed for concurrent use with the targeted radionuclide therapy [177Lu]Lu-octreotate (PRRT), forming a synergistic treatment strategy termed “combination [177Lu]Lu-octreotate-capecitabine-temozolomide radiopeptide chemotherapy.” The administration protocol is as follows: each treatment cycle lasts 8 weeks, with capecitabine administered at 1500 mg/m²/day (orally, twice daily) for 14 consecutive days, and temozolomide at 200 mg/m²/day (orally, once daily) for 5 consecutive days (typically scheduled on days 10–14). Concurrently, [177Lu]Lu-octreotate is administered intravenously at a dose of 7.9 GBq per cycle. The complete treatment comprises 4 cycles. This regimen is primarily applied in patients with advanced progressive or refractory pancreatic neuroendocrine tumors and represents a well-tolerated, highly effective outpatient treatment modality, achieving an 80% overall response rate with limited grade 3 thrombocytopenia (10%) and anemia (10%) [129]. For renal protection, mixed amino acid infusions (lysine and arginine) reduce radiopharmaceutical renal uptake by competitively inhibiting megalin receptor binding and promoting diuresis. This protective method is also applied when using radiopeptides such as [177Lu]Lu-PSMA-I&T alone [52, 110, 130].
Temporal order effect: the key to unlocking synergistic effects
Spatiotemporal sequence design determines efficacy-toxicity balance. The immune priming window following radiotherapy-induced immune response requires timely checkpoint inhibitor combination. Chen et al.‘s scRNA-seq analysis showed combination therapy significantly increased intratumoral CD8 + T cells and NK cells while reducing regulatory T cells (Fig. 6A) [103]. Radiosensitization strategies optimize radioisotope effects through fractionated dosing. Arbuznikova et al. demonstrated EBRT first enhancing PSMA expression, followed by [177Lu]Lu-PSMA-617 injection, improving tumor uptake and reducing toxicity (Fig. 6B) [118].
Biomarker guidance
Precise patient identification requires efficacy predictive biomarkers and dynamic resistance monitoring [133, 134].
Efficacy predictive markers
Molecular imaging using PSMA-PET demonstrated that patients with SUVmean ≥ 10 achieved 91% PSA response rate with [177Lu]Lu-PSMA-617 versus 47% with cabazitaxel, with significantly prolonged rPFS (HR = 0.46, 95%CI 0.25–0.84). However, no significant difference was observed in low expression groups (Fig. 6D) [132]. Violet et al. confirmed patients with absorbed doses ≥ 14 Gy achieved 76.5% PSA50 response versus 9.1% in < 10 Gy group [135].
Liquid biopsy monitoring revealed patients with baseline alkaline phosphatase > UNL had median OS of 28 months, 13 months shorter than normal groups (Fig. 6C) [131].Tumor heterogeneity assessment using SSTR-PET showed large-volume low-uptake lesions (TUQ50 > 0.05) increased PFS shortening risk by 50% [131].
Dynamic resistance monitoring
ctDNA analysis revealed AR gene amplification rates in non-responders significantly exceeded responders (56.3% vs. 39.3%) [136]. CTC functional analysis showed cells with low antioxidant capacity (TAC < 0.5mM, GSH<5nmol/mg) demonstrated improved [177Lu]Lu-DOTA-TATE sensitivity, with survival rates decreased by 33% [137, 138].
Through integrated application of these biomarker-guided approaches, combination therapy optimization can achieve enhanced efficacy while minimizing toxicity risks.
Combining 177Lu radiopharmaceuticals with chemotherapy and immunotherapy demonstrates significant synergistic effects in advanced cancers, including mCRPC and neuroendocrine tumors. However, this strategy presents challenges including cumulative toxicity, sequence dependency, and individual variability. This analysis examines core challenges and proposes optimization recommendations for toxicity management, temporal effects, and biomarker-guided approaches [125, 126].
Toxicity management
Combination therapy enhances efficacy through synergistic mechanisms but increases toxicity due to overlapping mechanisms [127]. The AlphaBet trial protocol highlights that the combination of 223Ra and [177Lu]Lu-PSMA-I&T in metastatic castration-resistant prostate cancer may exhibit higher hematologic toxicity compared to monotherapy: up to 13% anemia (grade 3 or higher in 8–13%) and 7% neutropenia (grade 3 or higher in 2.5–7%) versus lower rates in single-agent controls; thrombocytopenia could rise to 13% (grade 3 or higher in 6–8%) relative to 1–6% in controls, driven by overlapping myeloid suppression mechanisms [128].
Optimization strategies include Optimization strategies include Claringbold’s CAPTEM regimen. The CAPTEM regimen refers to an oral chemotherapy combination of capecitabine and temozolomide. In the literature by Claringbold et al., it was designed for concurrent use with the targeted radionuclide therapy [177Lu]Lu-octreotate (PRRT), forming a synergistic treatment strategy termed “combination [177Lu]Lu-octreotate-capecitabine-temozolomide radiopeptide chemotherapy.” The administration protocol is as follows: each treatment cycle lasts 8 weeks, with capecitabine administered at 1500 mg/m²/day (orally, twice daily) for 14 consecutive days, and temozolomide at 200 mg/m²/day (orally, once daily) for 5 consecutive days (typically scheduled on days 10–14). Concurrently, [177Lu]Lu-octreotate is administered intravenously at a dose of 7.9 GBq per cycle. The complete treatment comprises 4 cycles. This regimen is primarily applied in patients with advanced progressive or refractory pancreatic neuroendocrine tumors and represents a well-tolerated, highly effective outpatient treatment modality, achieving an 80% overall response rate with limited grade 3 thrombocytopenia (10%) and anemia (10%) [129]. For renal protection, mixed amino acid infusions (lysine and arginine) reduce radiopharmaceutical renal uptake by competitively inhibiting megalin receptor binding and promoting diuresis. This protective method is also applied when using radiopeptides such as [177Lu]Lu-PSMA-I&T alone [52, 110, 130].
Temporal order effect: the key to unlocking synergistic effects
Spatiotemporal sequence design determines efficacy-toxicity balance. The immune priming window following radiotherapy-induced immune response requires timely checkpoint inhibitor combination. Chen et al.‘s scRNA-seq analysis showed combination therapy significantly increased intratumoral CD8 + T cells and NK cells while reducing regulatory T cells (Fig. 6A) [103]. Radiosensitization strategies optimize radioisotope effects through fractionated dosing. Arbuznikova et al. demonstrated EBRT first enhancing PSMA expression, followed by [177Lu]Lu-PSMA-617 injection, improving tumor uptake and reducing toxicity (Fig. 6B) [118].
Biomarker guidance
Precise patient identification requires efficacy predictive biomarkers and dynamic resistance monitoring [133, 134].
Efficacy predictive markers
Molecular imaging using PSMA-PET demonstrated that patients with SUVmean ≥ 10 achieved 91% PSA response rate with [177Lu]Lu-PSMA-617 versus 47% with cabazitaxel, with significantly prolonged rPFS (HR = 0.46, 95%CI 0.25–0.84). However, no significant difference was observed in low expression groups (Fig. 6D) [132]. Violet et al. confirmed patients with absorbed doses ≥ 14 Gy achieved 76.5% PSA50 response versus 9.1% in < 10 Gy group [135].
Liquid biopsy monitoring revealed patients with baseline alkaline phosphatase > UNL had median OS of 28 months, 13 months shorter than normal groups (Fig. 6C) [131].Tumor heterogeneity assessment using SSTR-PET showed large-volume low-uptake lesions (TUQ50 > 0.05) increased PFS shortening risk by 50% [131].
Dynamic resistance monitoring
ctDNA analysis revealed AR gene amplification rates in non-responders significantly exceeded responders (56.3% vs. 39.3%) [136]. CTC functional analysis showed cells with low antioxidant capacity (TAC < 0.5mM, GSH<5nmol/mg) demonstrated improved [177Lu]Lu-DOTA-TATE sensitivity, with survival rates decreased by 33% [137, 138].
Through integrated application of these biomarker-guided approaches, combination therapy optimization can achieve enhanced efficacy while minimizing toxicity risks.
Conclusions and outlook
Conclusions and outlook
177Lu-based radiopharmaceuticals have advanced nuclear medicine by leveraging their dual β- and γ-emissions for targeted therapy and SPECT imaging. Current preparation techniques achieve > 98% radiochemical stability using chelators such as DOTA. Clinically, [177Lu]Lu-DOTA-TATE has shown meaningful therapeutic benefit in neuroendocrine tumors (NETTER-1) [52], and [177Lu]Lu-PSMA-617 has improved survival in metastatic prostate cancer (VISION) [51].
Despite these successes, monotherapy remains limited by tumor heterogeneity, uneven dose deposition, and resistance. Combination strategies—chemotherapy, immunotherapy, and external radiotherapy—offer synergistic potential but require optimization to address toxicity accumulation, treatment-timing dependence, and patient-specific variability.
Future development directions
Targeted carrier design
Multispecific carriers (e.g., PSMA/GRPR bispecific ligands) and microenvironment-responsive systems (e.g., pH-sensitive release) can improve tumor targeting and penetration [139].
AI and computational optimization
Deep learning–based ligand–target modeling enables prediction of binding affinity and structural compatibility, accelerating rational radiopharmaceutical design [140].
Immune synergy and microenvironment modulation
Combining 177Lu with checkpoint inhibitors, STING agonists, or 177Lu-labeled antibodies targeting suppressive immune cells (e.g., CD206⁺ TAMs) may reshape the tumor microenvironment and enhance efficacy [80, 141].
Precision therapy optimization
Integrating AI with SPECT/CT and liquid biopsy allows dynamic treatment adaptation, refinement of immune-priming windows, and improved radiosensitization [142].
Multimodal integration
Novel combinations—including gold nanoparticles, α-emitters such as 225Ac, and metabolic inhibitors—offer opportunities to overcome radioresistant or bulky tumors.
Organoid model-driven optimization
Patient-derived organoids provide realistic tumor models for dose prediction, treatment screening, and resistance mechanism analysis [143].
177Lu radiopharmaceuticals are evolving from single-agent therapy toward multimodal, synergistic strategies. Through advances in carrier design, computational optimization, immune modulation, precision monitoring, and translational tumor models, key challenges of heterogeneity, resistance, and toxicity can be addressed, accelerating progress toward personalized radiotheranostics with improved clinical outcomes.
177Lu-based radiopharmaceuticals have advanced nuclear medicine by leveraging their dual β- and γ-emissions for targeted therapy and SPECT imaging. Current preparation techniques achieve > 98% radiochemical stability using chelators such as DOTA. Clinically, [177Lu]Lu-DOTA-TATE has shown meaningful therapeutic benefit in neuroendocrine tumors (NETTER-1) [52], and [177Lu]Lu-PSMA-617 has improved survival in metastatic prostate cancer (VISION) [51].
Despite these successes, monotherapy remains limited by tumor heterogeneity, uneven dose deposition, and resistance. Combination strategies—chemotherapy, immunotherapy, and external radiotherapy—offer synergistic potential but require optimization to address toxicity accumulation, treatment-timing dependence, and patient-specific variability.
Future development directions
Targeted carrier design
Multispecific carriers (e.g., PSMA/GRPR bispecific ligands) and microenvironment-responsive systems (e.g., pH-sensitive release) can improve tumor targeting and penetration [139].
AI and computational optimization
Deep learning–based ligand–target modeling enables prediction of binding affinity and structural compatibility, accelerating rational radiopharmaceutical design [140].
Immune synergy and microenvironment modulation
Combining 177Lu with checkpoint inhibitors, STING agonists, or 177Lu-labeled antibodies targeting suppressive immune cells (e.g., CD206⁺ TAMs) may reshape the tumor microenvironment and enhance efficacy [80, 141].
Precision therapy optimization
Integrating AI with SPECT/CT and liquid biopsy allows dynamic treatment adaptation, refinement of immune-priming windows, and improved radiosensitization [142].
Multimodal integration
Novel combinations—including gold nanoparticles, α-emitters such as 225Ac, and metabolic inhibitors—offer opportunities to overcome radioresistant or bulky tumors.
Organoid model-driven optimization
Patient-derived organoids provide realistic tumor models for dose prediction, treatment screening, and resistance mechanism analysis [143].
177Lu radiopharmaceuticals are evolving from single-agent therapy toward multimodal, synergistic strategies. Through advances in carrier design, computational optimization, immune modulation, precision monitoring, and translational tumor models, key challenges of heterogeneity, resistance, and toxicity can be addressed, accelerating progress toward personalized radiotheranostics with improved clinical outcomes.
출처: PubMed Central (JATS). 라이선스는 원 publisher 정책을 따릅니다 — 인용 시 원문을 표기해 주세요.
🏷️ 같은 키워드 · 무료전문 — 이 논문 MeSH/keyword 기반
- A Phase I Study of Hydroxychloroquine and Suba-Itraconazole in Men with Biochemical Relapse of Prostate Cancer (HITMAN-PC): Dose Escalation Results.
- Self-management of male urinary symptoms: qualitative findings from a primary care trial.
- Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years.
- Diagnostic accuracy of Ga-PSMA PET/CT versus multiparametric MRI for preoperative pelvic invasion in the patients with prostate cancer.
- Association of patient health education with the postoperative health related quality of life in low- intermediate recurrence risk differentiated thyroid cancer patients.
- Early local immune activation following intra-operative radiotherapy in human breast tissue.