A novel AIE photosensitizer for combination photodynamic immunotherapy via autophagy activation and tumor microenvironment modulation

The limited efficacy of cancer immunotherapy is often attributed to insufficient tumor immunogenicity and the presence of an immunosuppressive tumor microenvironment (ITM). To address these challenges, we developed a novel photosensitizer (PS), TTVBO-1MT, by conjugating the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor 1-methyl-d-tryptophan (1-MT) to the aggregation-induced emission (AIE) PS TTVBO via a glutathione (GSH)-responsive linker. Comprehensive in vitro and in vivo evaluations using a model of triple-negative breast cancer revealed that TTVBO-1MT exhibited potent antitumor activity. Mechanistic studies demonstrated that TTVBO-1MT mediated photoimmunotherapy through dual mechanisms involving autophagy induction and IDO1 inhibition. The photodynamic effect led to the induction of immunogenic cell death (ICD), while the glutathione-responsive release of 1-MT suppressed IDO1 activity, decreased Foxp3 expression, and reduced regulatory T cell (Treg) populations, thereby mitigating immunosuppression. This combined effect promoted T-cell infiltration and triggered a systemic antitumor immune response. Overall, the results suggest that TTVBO-1MT enables autophagy-assisted immuno-photodynamic modulation of the tumor microenvironment (TME), offering significant therapeutic potential.