LDRT combined with anti-PD-1 promotes tumor regression in head and neck squamous cell carcinoma through tumor metaprogram evolution and immune cell reprogramming.
[BACKGROUND] Anti–PD-1 (αPD-1) therapy shows limited efficacy in head and neck squamous cell carcinoma (HNSCC), partly due to an immunosuppressive tumor microenvironment (TME) and insufficient infiltr
APA
Li G, Yang X, et al. (2026). LDRT combined with anti-PD-1 promotes tumor regression in head and neck squamous cell carcinoma through tumor metaprogram evolution and immune cell reprogramming.. Journal of experimental & clinical cancer research : CR, 45(1). https://doi.org/10.1186/s13046-026-03660-3
MLA
Li G, et al.. "LDRT combined with anti-PD-1 promotes tumor regression in head and neck squamous cell carcinoma through tumor metaprogram evolution and immune cell reprogramming.." Journal of experimental & clinical cancer research : CR, vol. 45, no. 1, 2026.
PMID
41673717
Abstract
[BACKGROUND] Anti–PD-1 (αPD-1) therapy shows limited efficacy in head and neck squamous cell carcinoma (HNSCC), partly due to an immunosuppressive tumor microenvironment (TME) and insufficient infiltration of effector T cells. Low-dose radiotherapy (LDRT) has been suggested to modify the TME, potentially enhancing the effects of αPD-1.
[METHODS] We profiled murine HNSCC treated with LDRT (1 Gy) and/or αPD-1 using single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq), complemented by orthogonal functional assays and in situ validation (spatial transcriptomics and multiplex immunofluorescence).
[RESULTS] LDRT and αPD-1 synergistically suppressed tumor growth and remodeled the TME. Single-cell analyses showed malignant programs shifting from proliferative states toward stress- and interferon (IFN)-responsive states. Integrated scTCR-seq analysis revealed enhanced clonal expansion of tumor-reactive CD8⁺ T-cell subsets and reduced the frequency of CD4⁺ Treg-Ctla4 under combination therapy. TCR-based metrics (including STARTRAC) indicated higher migration potential and limited intratumoral clonal overlap for CD4⁺ Treg-Ctla4. An macrophage state (Macro-Isg15) was positively associated with CD4⁺ Treg-Ctla4 frequency and was more prominent under αPD-1 monotherapy. Ligand–receptor inference highlighted a Macro-Isg15–associated CXCL14–CXCR4 chemokine axis enriched under αPD-1 monotherapy and attenuated in LDRT-containing regimens, suggesting reduced chemokine-driven support for CD4⁺ Treg-Ctla4 accumulation/recruitment.
[CONCLUSION] These findings support an integrated framework in which LDRT augments αPD-1 efficacy by reprogramming malignant states and reshaping immune cell dynamics, including attenuation of immunosuppressive features within the TME. This preclinical evidence provides a rationale for translational evaluation of LDRT-based combination strategies in HNSCC.
[GRAPHICAL ABSTRACT] [Image: see text]
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13046-026-03660-3.
[METHODS] We profiled murine HNSCC treated with LDRT (1 Gy) and/or αPD-1 using single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq), complemented by orthogonal functional assays and in situ validation (spatial transcriptomics and multiplex immunofluorescence).
[RESULTS] LDRT and αPD-1 synergistically suppressed tumor growth and remodeled the TME. Single-cell analyses showed malignant programs shifting from proliferative states toward stress- and interferon (IFN)-responsive states. Integrated scTCR-seq analysis revealed enhanced clonal expansion of tumor-reactive CD8⁺ T-cell subsets and reduced the frequency of CD4⁺ Treg-Ctla4 under combination therapy. TCR-based metrics (including STARTRAC) indicated higher migration potential and limited intratumoral clonal overlap for CD4⁺ Treg-Ctla4. An macrophage state (Macro-Isg15) was positively associated with CD4⁺ Treg-Ctla4 frequency and was more prominent under αPD-1 monotherapy. Ligand–receptor inference highlighted a Macro-Isg15–associated CXCL14–CXCR4 chemokine axis enriched under αPD-1 monotherapy and attenuated in LDRT-containing regimens, suggesting reduced chemokine-driven support for CD4⁺ Treg-Ctla4 accumulation/recruitment.
[CONCLUSION] These findings support an integrated framework in which LDRT augments αPD-1 efficacy by reprogramming malignant states and reshaping immune cell dynamics, including attenuation of immunosuppressive features within the TME. This preclinical evidence provides a rationale for translational evaluation of LDRT-based combination strategies in HNSCC.
[GRAPHICAL ABSTRACT] [Image: see text]
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13046-026-03660-3.
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