Multimodal cascade-amplified phototheranostics for enhanced anti-tumor immunity
Liang Chen, Jierou Huang, Li Liu, Ming Tong, Xinchun He, Shaojing Zhao, Qingxu Diao, Haiou Chen, Jie Zeng, Minhuan Lan, Jianing Yi
Abstract
Effective immuno-photodynamic therapy (IPDT) is impeded by the limitations of monotherapy approaches, inadequate immune activation, and an immunosuppressive tumor microenvironment (TME). Here, we present a multifunctional phototheranostic nanoplatform based on an A-D-A type photovoltaic molecule (ITCC), which self-assembles into water-soluble nanoparticles (ITCC NPs) via DSPE-PEG–NH 2 –2000. Upon near-infrared (NIR) irradiation, ITCC NPs generate reactive oxygen species (ROS) and heat, enabling synergistic photodynamic therapy (PDT) and photothermal therapy (PTT), thereby sequentially triggering immunogenic cell death (ICD), activating the cGAS-STING pathway, and promoting vascular normalization. These cascade effects collectively promote dendritic cells (DCs), natural killer (NK) and T cell activation and infiltration, suppress regulatory T (Treg) cells, and reprogram both systemic and tumor immune microenvironments. Co-administration of the immune checkpoint inhibitor anti-TIGIT (aTIGIT), targeting phototherapy-induced exhausted TIGIT + NK cells, further potentiates antitumor efficacy. Metabolomic analysis reveals ITCC NP-induced reprogramming of tyrosine and lipid metabolism, potentially relieving immunosuppressive metabolic stress and enhancing antitumor immunity. In summary, ITCC NPs function as a single-component, NIR-activated nanoplatform that elicits synergistic phototherapeutic and immunomodulatory effects for cascade amplification of antitumor immunity. Their therapeutic potential is also validated in human hepatocellular carcinoma and breast cancer organoid models. This work presents a single-component, NIR-activated nanoplatform (ITCC NPs) that integrates synergistic photodynamic and photothermal therapies to sequentially induce immunogenic cell death, activate cGAS-STING signaling, and promote vascular normalization. Collectively, these processes remodel the immune microenvironment, achieving cascade-amplified antitumor immunity. When combined with anti-TIGIT immunotherapy, ITCC NPs significantly enhance therapeutic efficacy, representing a promising strategy for precision phototheranostics in cancer treatment. • Single-component ITCC NPs integrate PDT and PTT, achieving synergistic tumor ablation and enhanced antitumor immunity. • Sequential cascade-amplified immune activation via ICD induction, cGAS–STING pathway activation and vascular normalization. • Phototherapy-driven tumor metabolic reprogramming further augmented antitumor immune responses. • Combination with anti-TIGIT immune checkpoint blockade markedly enhanced in vivo antitumor efficacy.