PANoptosis-Driven Immunogenic Cell Death by a Single NIR Laser-Triggered Nanoplatform for Cancer Phototherapy
Immuno-phototherapy faces a critical bottleneck: achieving high singlet oxygen (1O2) quantum yield and efficient photothermal conversion simultaneously under a single near-infrared (NIR) laser. Here, we report an acceptor-donor-acceptor (A-D-A) structured molecule, 3,9-bis(2-methylene-((3-(1,1-dicyanomethylene)-6/7-methyl)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3-d:2',3'-d']-s-indaceno[1,2-b:5,6-b']-dithiophene (m-ITIC), formulated into nanoparticles (NPs) via self-assembly with DSPE-PEG-NH2. The NPs exhibit strong NIR absorption and fluorescence at 688 and 768 nm, respectively. Under single-laser irradiation, they generate heat, superoxide anion (O2•−), and 1O2, with a 1O2 quantum yield of 56.8% and photothermal conversion efficiency (PCE) of 27.4%. This enables NIR fluorescence imaging-guided synergistic photodynamic therapy (PDT) and photothermal therapy (PTT). Notably, the nanoplatform induces PANoptosis—a coordinated cell death program integrating pyroptosis, apoptosis, and necroptosis—in tumor cells, amplifying immunogenic cell death (ICD). This triggers robust dendritic cell activation, macrophage polarization toward M1 phenotype, elevated CD8+ T cell infiltration, and suppression of immunosuppressive Treg cells, leading to significant tumor growth inhibition and prevention of lung metastasis in vivo. Therapeutic efficacy was validated in patient-derived tumor organoids, underscoring translational potential. This study presents a novel single-laser-activated nanoplatform that simultaneously mediates efficient photothermal and photodynamic effects and induces PANoptosis-driven ICD for synergistic cancer immunotherapy.