PANoptosis driven immunogenic cell death by a single NIR laser triggered nanoplatform for cancer phototherapy

It remains a major challenge in phototherapeutics to achieve a high quantum yield of singlet oxygen generation and efficient photothermal conversion using a single near-infrared laser for immuno-phototherapy. To bridge this gap, we utilized 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), and formulated it into nanoparticles (NPs) by assembling with distearoylphosphatidylethanola-mine-polyethylene glycol-amino (DSPE-PEG-NH2). At 688 and 768 nm, these NPs present significant near-infrared absorption and fluorescence. They simultaneously generate heat, O2−•, and 1O2, with the 1O2 generation quantum yield of 56.8% and photothermal conversion efficiency (PCE) of 27.4%, enabling them excellent near-infrared (NIR) fluorescence imaging guided synergic photodynamic therapy (PDT) and photothermal therapy (PTT) capabilities. Importantly, this nanoplatform induces PANoptosis, a coordinated cell death program integrating pyroptosis, apoptosis, and necroptosis, in tumor cells, thereby amplifying immunogenic cell death (ICD) and enhancing antitumor immune responses. The combined effects lead to robust dendritic cell activation, macrophage polarization toward the M1 phenotype, elevated CD8+ T cell infiltration, and suppression of immunosuppressive Treg cells, resulting in significant tumor growth inhibition and prevention of lung metastasis in vivo. Furthermore, the therapeutic efficacy was validated in patient-derived tumor organoids, demonstrating translational potential. This study presents a novel strategy for NIR light-guided cancer phototherapy, wherein a single laser-activated nanoplatform simultaneously mediates efficient photothermal and photodynamic effects and induces PANoptosis driven ICD for synergistic cancer immunotherapy.