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

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.