Pulsed photobiomodulation reprograms the tumor immune microenvironment to restore local T cell-mediated antitumor immunity.

Developing strategies to precisely modulate the tumor immune microenvironment (TME) is crucial for advancing immunotherapy. Here, we reported that 980-nm pulsed photobiomodulation (PBM) inhibits early tumor growth by locally reinvigorating antitumor immunity, without direct cancer cell cytotoxicity. In syngeneic LLC and MC38 models, daily PBM delayed tumor growth and conferred durable protection upon rechallenge without systemic toxicity, while efficacy was dependent on CD8+ T cells. Single-cell RNA sequencing and flow cytometry revealed that PBM directly alleviates CD8+ T cell exhaustion and enhances their cytotoxic function in a regulatory T cell (Treg)-independent manner, with immunomodulatory effects restricted to irradiated tumor sites, whereas contralateral, untreated lesions remained unaffected, confirming a localized mode of immune modulation. PBM failed against pigmented B16 melanoma, likely due to melanin-mediated light absorption. Collectively, 980-nm pulsed PBM is a localized photo-immunomodulatory strategy that reinvigorates CD8+ T cells, holding potential as a safe adjunct to existing immunotherapies.