Simultaneous Reversal of T Lymphocytes and Cancer Cells Metabolism Via a Biomimetic Heavy‐Atom‐Free Photosensitizers‐Based Combination Therapies to Boost Cancer Photoimmunotherapy

Abstract

Abstract Near‐infrared (NIR) activated photosensitizers based on heavy‐atom‐free have great advantages in photoimmunotherapy, yet the tumor microenvironment often restricts their efficacy. To address this, a NIR‐activated heavy‐atom‐free photosensitizer (named Cy‐BF) is developed. Cy‐BF is then encapsulated with phospholipids and platelet exosome vesicles to create platelet exosomes vesicles biomimetic and Cy‐BF loaded hybrid liposomes (named CHL) Characterized by high phototoxicity, low dark toxicity, and enhanced tumor targeting, CHL demonstrates aggregation‐induced broadening of absorption spectra and NIR (760 nm laser) activates photothermal therapy and type I photodynamic therapy. The CHL‐mediated phototherapy induces mitochondrial damage and immunogenic cell death in tumor cells, decreases lactate production, and alters the tumor microenvironment by reducing regulatory T cells and increasing CD8 + T cells. To mitigate T cell inhibition by excess lactate, a combination therapy is introduced using lithium carbonate, which repurposes lactate as an energy source for CD8 + T cells, thereby enhancing the effectiveness of CHL‐mediated photoimmunotherapy. This combination approach represents a novel strategy for reversing lactate metabolism in both tumor cells and T cells, paving the way for future clinical applications in photoimmunotherapy.