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

Effective and safe modulation of the tumor immune microenvironment (TME) remains a key challenge in immunotherapy. Here, we show that 980 nm pulsed photobiomodulation (PBM) suppresses early-stage tumor progression by reprogramming local immune networks rather than by direct cytotoxicity. In syngeneic MC38 colon carcinoma models, daily PBM significantly delayed tumor growth and established durable protection upon rechallenge without systemic toxicity. The antitumor effect was completely lost in T cell–deficient mice, demonstrating strict dependence on adaptive immunity. Single-cell RNA sequencing and multiparameter flow cytometry revealed that PBM reduced both the frequency and suppressive phenotype of intratumoral regulatory T cells (Tregs) and alleviated CD8+ T cell exhaustion, shifting the local effector–regulatory balance toward functional immune activation. PBM acted only at the illuminated tumor site, whereas contralateral, untreated lesions remained unaffected, confirming a localized mode of immune modulation. PBM had no measurable effects on tumor cell viability in vitro, indicating that its efficacy derives from host–tumor interactions. The approach was ineffective against pigmented B16 melanoma, likely due to melanin-mediated light absorption, but was otherwise well tolerated. These findings define pulsed PBM as a non-pharmacological, photo-immunomodulatory strategy that locally restores T cell function, mitigates immune exhaustion, and establishes antitumor memory. PBM may complement existing T cell–based immunotherapies to enhance depth and durability of response with minimal systemic toxicity.