Enhancing tumor immunotherapy via photodynamic therapy with a cascade reaction of reactive oxygen species and sustaining nutrient supply

Photo-immunotherapy is a promising strategy for the treatment of malignancies; however, its efficacy is often limited by the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME). TME is typically deficient in L-arginine (L-Arg), which negatively impacts T cell survival and function. To address this issue, we developed a novel drug delivery system based on the multi-vesicular liposomes (MVLs) loaded with photosensitizer indocyanine green (ICG) and L-Arg (R), named R-ICG@MVLs. Under near-infrared (NIR) light irradiation, the PDT-mediated cascade reaction of reactive oxygen species (ROS) could oxidize a portion of L-Arg to generate NO, thereby inducing immunogenic tumor cell death (ITCD) and stimulating anti-tumor immune responses, including antigen-presenting cells (APCs) recruitment and T cells activation. Subsequently, R-ICG@MVLs continued to release L-Arg, which improved the immunosuppressive TME, providing nutritional support for the tumor-infiltrating T cells and thus enhancing their anti-tumor efficacy. Additionally, the photo -thermal effect of ICG could accelerate the membrane rearrangement of R-ICG@MVLs and produce multiple drug-loaded nanovesicles, thus enabling the NIR-controlled accelerated drug release. The formation of drug-loaded nanovesicles led to deeper penetration and widened the range of ICD and TME improvement, achieving a "shrapnel effect". In conclusion, our strategy realized the dual effects of immune activation and nutrition sup-port, which might provide a clinically applicable reference for tumor immunotherapy.