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

Area of Science:

• Oncology
• Immunotherapy
• Photodynamic Therapy

Background:

• Microsatellite-stable (MSS) colorectal cancer is resistant to PD-1 blockade immunotherapy.
• This resistance is linked to a non-immunogenic tumor microenvironment.

Purpose of the Study:

• To develop a targeted photosensitizer for photodynamic therapy (PDT) to overcome PD-1 blockade resistance in MSS colorectal cancer.
• To evaluate the efficacy and immune-modulating effects of the photosensitizer Ce6-RWYD.

Main Methods:

• Development of an integrin α6-targeted photosensitizer, Ce6-RWYD.
• In vitro assessment of cytotoxicity and cellular damage.
• In vivo evaluation in a CT26 subcutaneous tumor model, including combination therapy with anti-PD-1.
• Assessment of tumor accumulation, retention, and immune microenvironment modulation.

Main Results:

• Ce6-RWYD demonstrated potent light-activated cytotoxicity with minimal dark toxicity, inducing immunogenic cell death and suppressing integrin α6 signaling.
• In vivo studies showed enhanced tumor accumulation and retention of Ce6-RWYD compared to NPe6.
• Ce6-RWYD-mediated PDT achieved significant antitumor efficacy, remodeled the tumor immune microenvironment, and was well-tolerated.
• Combination therapy with anti-PD-1 significantly improved antitumor outcomes, increasing CD8+ T-cell infiltration and reducing myeloid cells.

Conclusions:

• Ce6-RWYD-mediated PDT is a promising strategy to sensitize MSS colorectal cancer to PD-1 blockade.
• Targeted PDT can effectively remodel the tumor immune microenvironment, enhancing immunotherapy efficacy.