Acupuncture in remodeling the tumor microenvironment: current status and challenges.

1
Introduction
Cancer remains the second leading cause of death globally. Morbidity and mortality are still increasing worldwide. In 2025, 2.04 million new cases and 618120 deaths occurred in the U.S. cancer statistics project (1). These numbers translate into unsustainable healthcare costs and identify urgent public health priorities.
Multimodal regimens have replaced monotherapy. Surgery, radiotherapy, and systemic agents are now combined patient-by-patient, doubling 5-year survival relative to single-modality eras (2). Yet, the heterogeneity among patients precludes true precision medicine (3). Acquired resistance and off-target toxicities further limit survival gains (4, 5). Consequently, dissecting clonal evolution and microenvironmental crosstalk are prerequisites for next-generation interventions.
The tumor microenvironment (TME) is an integral component of tumors and is widely recognized for its dynamic role in regulating cancer progression and influencing treatment efficacy (6). It integrates immune infiltration, cytokine gradients, extracellular matrix, and aberrant vasculature. Together, they promote chronic inflammation, immune evasion, and neovascularization (7). By cultivating resistance and exacerbating off target toxicity, TME reduces cytotoxicity and the efficacy of targeted drugs resistance and exacerbating off-target toxicity, the TME curtails the efficacy of cytotoxic and targeted agents (8). Therefore, the focus of treatment has shifted from tumor centered to TME centered strategies.
Acupuncture, a minimally invasive neuromodulatory stimulus, evokes systemic reflexes. It has been reported to ameliorate infection, allergy, autoimmunity, and immunodeficiency (9). Favorable safety profiles underlie its increasing clinical adoption (10). In oncology, acupuncture augments anti-tumor immunity, mitigates treatment-related toxicities, and improves quality-of-life metrics (11). Mechanistically, acupuncture triggers apoptosis of malignant cells and potentiates cytotoxic drugs (12). It further accelerates postoperative recovery through neuroendocrine regulation (13). Moreover, acupuncture reprograms intratumoral immune cells to restrain progression and metastasis (14). Collectively, acupuncture is becoming a targeted treatment modality for TME. Analyzing its multimodal impact on TME will provide information for evidence-based implementation. Here, we systematically synthesize recent advances in the mechanisms of acupuncture-mediated TME reprogramming and, using breast cancer as a case study, emphasize the importance of linking clinical symptom management with TME mechanisms. Converging data show that acupuncture restrains tumors by reprogramming TME cellularity and function, positioning it as a complementary therapeutic strategy. (see Figure 1)

2
Direct antitumor effects and combination therapy of acupuncture
Five decades of research have condensed cancer biology into eight hallmarks (15). These hallmarks include sustained proliferation, evasion of growth suppressors, apoptosis resistance, limitless replication, angiogenesis, and metastasis. Aberrant proliferation is the universal driver of malignancy. Resulting masses compress adjacent tissue, invade locally and seed distant organs. Tumor size predicts prognosis; invasion and metastasis dictate mortality (16, 17). Inducing cancer cell death remains the primary therapeutic goal. When conventional therapies fail, non-pharmacological options such as acupuncture are explored. Acupuncture reduces tumor volume by up to 45% in rat Walker-256 hepatoma, gastric and subcutaneous models (18). Osteosarcoma-bearing mice exhibit 30% slower growth when ≥3 acupoints are stimulated. These changes coincide with reduced densities of tumor vessels, lymphatics and nerves, and a 60% drop in pulmonary metastases (19, 20). Timing determines efficacy. Day-3 acupuncture suppresses tumor burden by 40%, whereas day-7 treatment doubles tumor volume (20). The therapeutic window is therefore confined to early-stage disease. Late-stage tumor promotion has not previously been reported. Prospective mapping of the time-dependency is now required.
Monotherapy inevitably selects for resistance. Rational combination strategies are therefore essential. First-line chemotherapy still depends on apoptosis induction (21). Electroacupuncture (EA) enhances cisplatin-mediated tumor suppression in patients with stage IIb–IIIb cervical squamous cell carcinoma, yielding greater tumor shrinkage than chemotherapy alone (22). The synergy stems from increased apoptosis. EA-capeOX doubles apoptotic index and maximally reduces tumor volume by day 7 (23). Beyond chemosensitization, acupuncture improves quality-of-life metrics and potentially extends survival (24). Evidence remains fragmented and tumor-centric. Robust trials and mechanistic insights are lacking. Multicenter, randomized, mechanism-anchored trials are now warranted.

3
Acupuncture and the tumor immune microenvironment
The tumor immune microenvironment (TIME) encompasses all immune constituents within the TME. These constituents interact to drive or suppress anti-tumor immunity (25). Immune cells dictate TIME status. Tumors are classified as ‘cold’ or ‘hot’ according to immune infiltration patterns (26). Cold tumors lack CTLs and evade immune surveillance. Hot tumors harbor activated CTLs, NK cells and DCs that mount effective anti-tumor responses. Immune cell density and diversity predict treatment response and survival (27, 28). Converting cold into hot tumors is now a research priority. Acupuncture remodels the TIME by boosting immunity and restoring homeostasis (29). This translates into improved outcomes and quality of life (14).
3.1
Adaptive immunity
The adaptive immune system eliminates specific antigens through clonally restricted receptors and effector molecules. Essential for anti-pathogen and anti-tumor immunity, it drives autoimmunity when dysregulated (30). T and B lymphocytes execute antigen-specific responses. In the TIME, inhibitory cytokines, exhausted lymphocytes and suppressive infiltrates paralyze adaptive immunity (31).
3.1.1
T lymphocytes
CD8+, CD4+ and Treg subsets dominate cancer immunotherapy studies. CD8+ T cells kill tumor cells via perforin/granzyme or FAS-FASL ligation. Intratumoral CD8+ density predicts survival. Pretreatment osteosarcoma biopsies (n=124) show that abundant CD8+ T cells correlate with longer overall survival (32). Merkel-cell carcinoma displays the same association (33). Chronic antigen exposure and epigenetic rewiring exhaust CD8+ T cells and impair tumor control (34). Hence, checkpoint monotherapy frequently fails (35). CD4+ T cells exert context-dependent pro- or anti-tumor activity (36). Th1 cells license CD8+ activity and secrete IL-2, TNF-α and IFN-γ. Th2 and Th17 cytokines instead fuel tumor growth. Tregs curb autoimmunity but also suppress anti-tumor immunit (37). In cancer, however, Tregs inhibit effector cell function, leading to immune evasion. Acupuncture expands and activates CD3+CD8+ pools while rebalancing CD4+ subsets.
EA increases splenic CD3+CD4+ and CD3+CD8+ T-cell subsets and plasma IL-2 levels, albeit with weaker analgesia than morphine, in a rat model of breast-cancer bone pain (38). Acupuncture preserves CD8+ T-cell numbers and reverses drug-induced immunosuppression in patients with metastatic bone pain (39). Acupuncture also preserves hematopoietic and immune function after chemotherapy. In 28 cancer patients, one month of acupuncture during chemotherapy maintained CD3+, CD4+, CD8+ counts and the CD4+/CD8+ ratio (40). EA alleviates chemotherapy-induced myelosuppression and reshapes TME immune infiltration and cytokine profiles in NSCLC mice (41, 42). EA expands peripheral hematopoietic stem and leukocyte subsets, indicating bone-marrow niche reconstruction. Intratumorally, EA increases CD8+ infiltration and IL-2/IFN-γ while curbing Th17 and Treg fractions. EA boosts bone-marrow sympathetic density and PACAP–PAC1 signaling, coupling hematopoietic protection to anti-tumor immunity (41). Cancer−related fatigue (CRF) affects >90% of patients during chemotherapy (43). IL-6 and IL-1-mediated neuroinflammation precipitate fatigue (44, 45). Leptin, a key hormone in energy metabolism, is concurrently elevated (46). Acupuncture suppresses leptin–AMPK signaling, rescues neuronal mitochondria and restores CD3+, CD4+ T cells and immunoglobulin levels, reversing fatigue (45).
Acupuncture also sensitizes tumors to immunotherapy. EA downregulates HDAC1, recruits CD8+ T cells and curbs triple-negative breast cancer growth (47). EA plus HDAC inhibitor achieves 60% tumor control, confirming TIME remodeling (48). MSS colorectal cancer, an immune-desert subtype, resists checkpoint blockade (49). EA plus anti–PD-1 converts MSS tumors from cold to hot (50). EA upregulates PD-L1, recruits CD8+ T cells and engages STING. Optimal immunomodulation occurs at 1.0 mA, coinciding with dampened neuronal firing. Thus, EA operates via the neuro-endocrine-immune axis (10, 51). Translation to randomized trials is now justified. Acupuncture enhances CD3+, CD4+ and CD8+ T-cell function, potentiates immunotherapy and depletes Th17 and Treg cells.

3.1.2
B lymphocytes
B cells underpin humoral immunity. They secrete antibodies that bind mutation-derived or post-translationally modified neoantigens. Activated B cells further license T cells via antigen presentation and co-stimulation (52). TME-derived signals impair B-cell proliferation, differentiation, antibody output and complement activation, enabling escape. Acupuncture rescues B-cell counts and rebalances immunoglobulin titers. It reverses chemotherapy- or analgesia-driven B-cell loss (39, 53). Antibody output is bidirectionally tuned by acupuncture. In autoimmunity (rheumatoid arthritis, obesity), acupuncture lowers IgG, IgA and IgM (54, 55). Conversely, in cancer-related immunosuppression, it raises IgG and IgM (56).

3.2
Innate immunity
Innate immunity mounts rapid, non-specific defenses that precede adaptive responses (57). These comprise physical barriers, effector cells and molecules that block pathogens and initiate downstream inflammation and adaptive immunity (58). NK cells, macrophages and dendritic cells clear pathogens, regulate inflammation and defend the host. Within the TIME, these cells suppress tumors via direct cytotoxicity or by priming adaptive immunity (59). Acupuncture boosts innate-cell numbers and activity, reinforcing anti-tumor defense.
3.2.1
Natural killer cells
Natural killer (NK) cells are innate cytotoxic lymphocytes that act as a first-line defense against neoplastic, senescent or infected cells. They eliminate target cells without prior sensitization, as they do not require antigen presentation (60). Cytotoxicity is mediated by perforin–granzyme exocytosis or by engagement of death receptors belonging to the tumor-necrosis factor (TNF) superfamily (61). Tumors progressively evade NK-cell surveillance by up-regulating inhibitory ligands and recruiting immunosuppressive myeloid and regulatory T cells (62). The effect of acupuncture on NK-cell number and function has been investigated in both clinical and pre-clinical settings. In patients with anxiety disorders, acupuncture restored NK-cell activity, which remained elevated for at least four weeks after the final session. In women with anxiety, NK cell activity remained elevated for one month following acupuncture treatment (63). EA attenuated surgery-induced immunosuppression in craniotomy patients, as evidenced by increased NK-cell counts and serum IgM/IgA (64). Collectively, these data indicate that acupuncture can re-establish NK-cell homeostasis in immunocompromised hosts.
It has been hypothesized that acupuncture augments anti-tumor immunity, at least in part, by activating NK cells (65). In post-operative colorectal-cancer patients, acupuncture increased the peripheral NK-cell fraction and was associated with improved gastrointestinal and immune recovery (66). Transcutaneous electrical acupoint stimulation restored NK-cell numbers in patients with non-small-cell lung cancer during the perioperative phase, and concurrently reduced plasma TNF-α and IL-6, stabilized hemodynamics, lowered anesthetic requirement and shortened hospitalisation (67). In chemotherapy-treated patients, acupuncture mitigated treatment-related immune suppression and preserved NK-cell cytolytic activity (53). In cyclophosphamide-treated mice, EA enhanced NK-cell cytotoxicity and increased systemic IL-2, IL-12, TNF-α and IFN-γ, an effect that was dependent on DREAM–NF-κB signaling (68). When EA was combined with chemotherapy in cervical-cancer patients, tumor control was improved and corresponded with expanded NK-cell pools and reduced lesion volume (22).
Pre-clinical data show that acupuncture modulates splenic and peripheral NK-cell compartments by releasing β-endorphin, dampening hypothalamic–pituitary–adrenal (HPA) axis output and activating vagal afferents (69). β-Endorphin, an endogenous opioid released during HPA-axis activation, reaches immune cells through the systemic circulation (70). Acupuncture-induced β-endorphin up-regulates perforin, granzymes and TNF-family ligands, and amplifies IFN-γ secretion by NK cells (71, 72). EA also activates choline-acetyltransferase-positive (ChAT+) neurons in the dorsal motor nucleus of the vagus, thereby increasing the NK-cell fraction and cytolytic capacity while curbing accumulation of myeloid-derived suppressor cells (MDSCs), and consequently retarding 4T1-luc2 breast-tumor growth in mice (73). Together, these pathways converge to strengthen NK-cell-dependent anti-tumor immunity.

3.2.2
Macrophages
Macrophages arise from bone-marrow hematopoietic stem cells and orchestrate phagocytosis, antigen presentation, inflammatory control and tissue homeostasis (74). In many solid tumors, macrophages account for up to 50% of the total cellularity (75). Macrophages polarize along a continuum, but are commonly classified into pro-inflammatory M1 or anti-inflammatory M2 extremes. Within the TIME, M1 macrophages restrain malignancy, whereas M2-polarised tumor-associated macrophages (TAMs) foster progression. M1 cells directly phagocytose malignant cells, trigger apoptosis and cross-talk with the adaptive arm by activating antigen-presenting cells and recruiting CD8+ T, Th1 and NK cells (76). Conversely, TAMs promote angiogenesis, suppress anti-tumor immunity, facilitate metastasis and blunt therapeutic efficacy (77). Therapeutic reprogramming of TAMs toward an M1-like state is therefore under intense investigation.
Acupuncture studies have interrogated macrophage abundance, polarization and secretory profiles. In a rat model of chronic obstructive pulmonary disease, acupuncture lowered macrophage counts in bronchoalveolar-lavage fluid, curtailed inflammatory infiltrates and improved lung mechanics (78). In rheumatoid-arthritis models, acupuncture mitigated inflammation and pain, effects linked to suppressed M1 polarization and reduced IL-1β (79). Peri-tumor electroacupuncture (EA) shifted TAM polarity toward an M1 phenotype, leading to decreased microvessel density, increased pericyte coverage and enhanced vascular maturation (80). This reprogramming was dependent on down-regulation of glyoxalase-1 (GLO1) and activation of the methylglyoxal–AGE/RAGE axis (81). These data provide the first demonstration that EA curtails angiogenesis by enforcing an M1-like TAM signature. The intersection of acupuncture and TAM biology remains exploratory and warrants mechanistic dissection.

3.2.3
Dendritic cells
Dendritic cells (DCs) integrate innate and adaptive immunity by acquiring, processing and presenting antigens that initiate and sculpt T-cell responses (82). In cancer hosts, DCs relay tumor antigens to effector T cells and secrete cytokines that license anti-tumor CD4+ and CD8+ T-cell immunity (83). Yet, defective DC differentiation or trafficking frequently blunts tumor-specific T-cell priming. In 4T1 mammary-tumor-bearing mice, acupuncture plus anti-PD-1 therapy synergistically curtailed tumor growth. This efficacy coincided with expansion of CD5+ DCs, systemic accumulation of CD4+ and CD8+ T cells and heightened IL-2, IL-6, TNF-α and IFN-γ concentrations (84). CD5, a transmembrane glycoprotein mandatory for optimal effector T-cell activation, is selectively induced on DCs by IL-6 (85). Acupuncture also shapes the local DC pool at acupoint sites, probably via neurogenic inflammation within dermal tissue (86).

3.2.4
Mast cells
Mast cells (MCs) are innate immune cells that reside in perivascular and perineural niches. They are best recognized for orchestrating allergic responses and anti-helminth immunity (87). Recent tumor-biology studies reveal that MC density and their inflammatory cargo within the tumor microenvironment (TME) exert context-dependent, dichotomous effects on gastrointestinal malignancies (88, 89). In pancreatic-cancer patients with visceral pain, peritumoral tissues exhibit elevated MC counts and high levels of histamine, tryptase and nerve growth factor (NGF), implicating MC degranulation in visceral hypersensitivity (90). MCs further amplify angiogenesis by releasing VEGF, FGF-2, PDGF and angiopoietin-1, thereby fueling tumor expansion (91). Acupuncture suppresses MC degranulation in both allergic and inflammatory settings. In a rat model of irritable-bowel syndrome, acupuncture curbed aberrant MC proliferation and activation in colonic mucosa, normalized substance P (SP) and vasoactive-intestinal-peptide (VIP) release and ameliorated visceral hypersensitivity (92). EA also attenuated MC infiltration and degranulation in atopic-dermatitis rats through cannabinoid CB2 receptors, concomitantly lowering IgE and other immune-active mediators (93). Acupuncture may further recruit endogenous opioid pathways to curb MC degranulation and relieve pain (94). These mechanisms collectively illustrate how acupuncture tunes MC-mediated immune responses.

4
Acupuncture and the vasculature in tumors
Angiogenesis is an obligate prerequisite for tumor expansion and metastatic spread (95). Initially, neoplastic cells rely on diffusion for nutrient uptake. Once the lesion exceeds ~2 mm, diffusion becomes insufficient and a dedicated vascular network must be forged to deliver oxygen and nutrients and to evacuate metabolic waste (96, 97). Tumor angiogenesis is orchestrated by a multicellular interplay among malignant cells, vascular cells and pro-angiogenic cues (98). Within the tumor microenvironment (TME), chronic overproduction of pro-angiogenic signals generates immature, chaotic and dysfunctional vascular beds. T These aberrant vessels are tortuous, hyperpermeable and inefficient, fostering hypoxia and lactate build-up (99). Sparse pericyte coverage and weakened endothelial–pericyte crosstalk further undermine vascular maturity and stability (100). Consequently, perfusion is impaired and drug delivery is compromised. Jain’s 2001 concept of vascular normalization posits that transient pharmacological repair, rather than destruction, of tumor vessels can curb metastasis and enhance drug delivery (101). Subsequent work indicates that acupuncture can reprogram vascular cells and angiogenic cues to normalize tumor vasculature.
4.1
Vascular endothelial cells
Endothelial cells (ECs) line the luminal surface of vessels and constitute the central cellular driver of angiogenesis. In healthy tissue, ECs are tightly juxtaposed, creating a selective vascular barrier. In tumors, ECs down-regulate adhesion molecules, adopt a loose configuration and thereby permit intravasation and metastatic dissemination (102). Paracellular leakage elevates interstitial fluid pressure, reducing perfusion, aggravating hypoxia and ultimately collapsing vessels (103). The resultant chaotic vasculature creates large, under-perfused and drug-inaccessible tumor regions (104). Emerging evidence shows that inhibition of glycolysis in tumor ECs can drive vascular normalisation (105, 106). As outlined above, endothelial GLO1 and the glycolytic methylglyoxal-detoxification axis are proximal targets of acupuncture (81). Acupuncture down-regulates GLO1, curbs angiogenesis and reinforces inter-endothelial junctions, peaking 72 h post-stimulus. Electroacupuncture-evoked decreases in glycolytic flux and methylglyoxal metabolites corroborate GLO1 as the proximal enzymatic target. Hypoxic tumor regions release VEGF, igniting pro-angiogenic signaling cascades (107). Acupuncture blunts tumor angiogenesis by down-regulating endothelial VEGF-A, VEGFR-2 and the co-receptor neuropilin-1 (NRP-1) (108). NRP-1, an obligate co-receptor for developmental vascular patterning, potentiates VEGFR signaling in ECs (109).
Beyond the tumor core, the blood–brain barrier (BBB) constitutes a formidable obstacle to brain-tumor therapy (110). Macromolecular therapeutics fail to achieve cerebrovascular penetration, and local delivery is constrained by surgical invasiveness and limited diffusion (111). The BBB is constituted by brain microvascular ECs joined by continuous tight junctions. Electroacupuncture delivered at 2/100 Hz, 3 mA, 6–6 s cycles for 40 min transiently opens the BBB, augments cerebral paclitaxel levels and potentiates anti-glioma activity (112, 113). The mechanism involves endothelial NMDA-receptor activation, Hedgehog-pathway modulation and occludin displacement at tight junctions. Whether BBB opening is acupoint-specific remains contentious. Some studies restrict efficacy to craniofacial acupoints (112), whereas others invoke a primitive vascular system (PVS) that links remote spinal or limb acupoints to the brain, bypassing the BBB (114).

4.2
Pericytes
Pericytes are mesenchymal mural cells that encase capillaries and crosstalk with ECs through juxtacrine and paracrine signals to sustain vascular maturation and stability (115). Within tumors, pericytes play paradoxical roles. They can impair drug delivery and immune access by increasing mural coverage of tumor vessels (116). Conversely, dense pericyte coverage can restrain tumor-cell dissemination (117). Peri-tumor acupuncture increases pericyte coverage and drives vascular normalization in superficial tumors. Acupuncture up-regulates α-SMA, expands differentiated functional vessels and leaves total vascular density unchanged (118). This normalization elevates intratumoral paclitaxel concentrations in murine breast-cancer models. Collectively, acupuncture functions as a biological navigation system that redistributes drugs within tumor tissue and amplifies therapeutic efficacy (119). Importantly, acupuncture outperforms anti-angiogenic agents in tightening endothelial junctions and expanding pericyte coverage (81), underscoring its adjunctive potential in combination regimens.

5
Acupuncture in breast cancer: TME mechanisms and symptom management
Breast cancer, the most prevalent malignancy in women worldwide, provides an ideal model for an “Acupuncture—TME Mechanism—Symptom Management” framework. This utility stems from its clearly defined molecular subtypes, distinctive TME features, diverse therapeutic options, and stage-dependent symptomatology.
5.1
Acupuncture mechanisms in different subtypes and symptom management
Based on HER2 and hormone receptor status, breast cancer is classified into three main subtypes: Luminal A/B, HER2-enriched, and triple-negative breast cancer (TNBC). This classification is clinically important because each subtype displays distinct tumor microenvironment (TME) heterogeneity, guiding different treatment approaches (120). Among these, TNBC—though aggressive and associated with poorer prognosis—often presents a more immunogenic TME, featuring higher levels of tumor-infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden, making it more amenable to immunotherapy (121). Preclinical studies suggest that acupuncture may promote tumor cell apoptosis and enhance immune cell infiltration (including CD5+ dendritic cells and CD4+/CD8+ T lymphocytes) in TNBC models, potentially synergizing with immunotherapies (84). In contrast, Luminal and HER2-enriched subtypes typically exhibit an immunologically “cold” TME with lower immune infiltration, which may limit their response to immunotherapy and reduce any direct immunomodulatory effects of acupuncture. However, acupuncture has been shown to effectively relieve treatment-related side effects in these patients—such as hot flashes, pain, neuropathy, fatigue, and myelosuppression—through modulation of neuro-inflammatory and neuro-endocrine-immune pathways (24). For example, in ovariectomized rat models, electroacupuncture has been found to significantly upregulate hypothalamic aromatase expression and activity at both the mRNA and protein levels. This modulation subsequently influences GnRH neuronal function, leading to an improvement in vasomotor symptoms (122). Furthermore, electroacupuncture can reduce the release of key pro-inflammatory cytokines, such as TNF-α and IL-1β, in both the spinal cord and peripheral circulation (123). While current evidence clarifies how acupuncture alleviates symptoms, it remains unclear whether these benefits involve direct or indirect effects on the TME. Future studies exploring the connection between symptom relief and TME reprogramming will be essential to integrate acupuncture effectively into comprehensive cancer care.

5.2
The advantage of acupuncture in perioperative care and long-term survivorship
Breast cancer patients frequently experience multiple, interconnected symptoms across various phases of treatment. These symptoms can act synergistically, thereby significantly impairing both quality of life and long-term outcomes. Research suggests that acupuncture exerts multifaceted advantages in integrated breast cancer management, mediated through neuromodulatory and anti-inflammatory actions from acupoints to target organs. During the perioperative period, acupuncture has been shown to not only reduce the incidence of chronic pain at six months post-mastectomy but also effectively decrease arm circumference and the sensation of swelling in lymphedema patients (124, 125). Furthermore, survivors who have completed comprehensive treatment often experience psychoneurological symptoms and persistent treatment-related side effects. These include sequelae of systemic therapy, fatigue, breast symptoms, sleep disturbances, and arm morbidity. Consequently, acupuncture is commonly utilized to manage this diverse symptom cluster in long-term survivorship care. A cross-sectional survey of 415 breast cancer survivors revealed that 82.1% of participants reported symptom improvement following acupuncture intervention (126). Collectively, these findings underscore the feasibility and potential of acupuncture within integrative survivorship care for symptom management, highlighting its role in improving the long-term prognosis of breast cancer patients.

6
Discussion
Acupuncture has achieved worldwide clinical acceptance because it is simple, safe and demonstrably effective. In oncology, trials have concentrated on symptomatic indications—pain, fatigue, nausea, hot flushes, neuropathy, myelosuppression and insomnia—and have employed manual, electro-, auricular or transcutaneous stimulation as well as moxibustion. Although an expanding corpus of randomized controlled trials supports its utility, robust evidence remains restricted to a narrow range of indications. Methodological challenges are intrinsic to acupuncture research: intervention standardization, sham control credibility, outcome selection and statistical powering all remain contested. Integrative studies employing molecular biology, single-cell cytomics and genomics now indicate that acupuncture can do more than palliate; it can directly restrain tumor growth by reprogramming the tumor micro-environment—augmenting apoptosis, quelling inflammation, activating immune cells, normalizing vasculature and improving drug delivery—effects that appear to be orchestrated through neuro-immune crosstalk. Yet mechanistic inquiry remains fragmentary, with most reports confined to immune modulation and few interrogating proximal signaling cascades or systems-level networks. Pre-clinical data sets are heterogeneous and under-powered, precluding rigorous dose–response definitions or immediate translational guidance.
The tumor microenvironment (TME) governs initiation, progression and therapeutic response, rendering it a prime anti-cancer target (127). Here we systematically dissect how acupuncture reshapes the TME to restrain malignancy. Acupuncture both triggers tumor-cell apoptosis and synergizes with cytotoxics while concurrently reprogramming the tumor-immune microenvironment (TIME) through multifarious pathways. These encompass amplifying T-cell and NK-cell infiltration, enforcing M1 macrophage polarization, bolstering dendritic-cell competence and tuning B-cell and mast-cell activity. Moreover, acupuncture normalizes tumor vasculature by reprogramming endothelial cells and pericytes, thereby augmenting drug delivery and anti-tumor efficacy. Collectively, these actions constitute a multi-scale network that underpins acupuncture-mediated TME reprogramming. For the surgical oncologist, these mechanisms translate into tangible clinical opportunities. The ability of acupuncture to manage perioperative symptoms can contribute to improved quality of life and potentially enhance long-term survival. Its efficacy in reducing postoperative pain and addressing survivorship issues such as lymphedema aligns with the growing emphasis on patient-centered, functional outcomes in breast cancer care. Therefore, future clinical trials should not only focus on traditional survival endpoints but also incorporate robust metrics of symptom management, functional recovery, and patient-reported outcomes, particularly in perioperative and survivorship settings.
Nevertheless, pivotal challenges persist. Dose–response curves remain undefined and standardized end-point frameworks are absent. Mechanistic enquiries have privileged immunomodulation, leaving proximal signaling cascades and neuro-endocrine-immune synapses largely uncharted. I Moreover, bench-to-bedside translation is sparse and rigorously powered randomized controlled trials remain scarce. Future work must fuse systems biology, immunology and neuroscience to decode the molecular and cellular circuitry through which acupuncture rewires the TME. Concurrently, standardized yet individualized protocols should be forged and validated in adequately powered trials that delineate synergies with cytotoxics, immune checkpoint inhibitors and other modalities across molecularly stratified cohorts. Collectively, acupuncture stands ready to assume a precise and impactful role within tomorrow’s multimodal oncology armamentarium.