Multimodal cascade-amplified phototheranostics for enhanced anti-tumor immunity

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-NH₂-2000. 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.

Keywords: Cascade-amplified phototheranostics; Immuno-photodynamic therapy; Immunogenic cell death; Photothermal therapy; Vascular normalization.