Integrin α6-targeted photodynamic therapy potentiates PD-1 blockade in MSS colorectal cancer

Microsatellite-stable (MSS) colorectal cancer is largely refractory to PD-1 blockade due to its weak immunogenicity and an immune-excluded tumor microenvironment. Here, we developed an integrin α6-targeted photosensitizer, Ce6-RWYD, for tumor-selective photodynamic therapy (PDT). Ce6-RWYD exhibited minimal dark toxicity but induced strong light-activated cytotoxicity, accompanied by plasma membrane damage. Ce6-RWYD-mediated PDT also induced mitochondrial dysfunction and immunogenic cell death, while suppressing integrin α6-related downstream signaling. In vivo fluorescence imaging demonstrated enhanced tumor accumulation and prolonged retention of Ce6-RWYD compared with the talaporfin sodium (NPe6). In a CT26 subcutaneous tumor model, Ce6-RWYD-mediated PDT achieved robust antitumor efficacy, remodeled the tumor immune microenvironment, and showed favorable in vivo biosafety. Combination with anti-PD-1 further enhanced antitumor efficacy, accompanied by increased intratumoral CD8⁺ T-cell infiltration and reduced Gr-1⁺ myeloid cells. Collectively, these findings demonstrate that Ce6-RWYD-mediated PDT sensitizes MSS colorectal cancer to PD-1 blockade.