Photothermal Sensitive Nano Heterojunction Triggering Ferroptosis and PANoptosis for Improving Tumor Immunotherapy

ABSTRACT Photodynamic therapy (PDT) and photothermal therapy (PTT) demonstrate considerable clinical potential in tumor treatment by inducing apoptosis through the generation of reactive oxygen species (ROS) and hyperthermia. However, their therapeutic efficacy is hampered by the inherent resistance of tumor cells to apoptotic pathways. Immunogenic cell death (ICD) modalities, such as ferroptosis and PANoptosis, circumvent this resistance by eliciting robust anti‐tumor immune responses. Nevertheless, conventional ICD inducers are plagued by suboptimal pharmacokinetics and dose‐dependent toxicity, necessitating the highly efficient, non‐toxic ferroptosis/PANoptosis activators. Herein, a bismuth‐based photothermal‐sensitive nano‐heterojunction (Bi 2 S 3 @Bi 2 Se 3 @Se‐PEG, BSSP) synergistically triggering ferroptosis and PANoptosis is constructed. BSSP minimizes charge recombination while enhancing catalytic activity. The pyroelectric properties of Bi 2 S 3 /Bi 2 Se 3 and selenium's photo/thermal sensitivity cooperatively amplify ROS production and achieve superior photothermal conversion efficiency to enhance both PDT and PTT. In the murine 4T1 breast cancer model, BSSP combined with near‐infrared irradiation significantly suppresses primary tumor growth, inhibits distal tumor proliferation, and attenuates pulmonary metastasis. Moreover, BSSP remodels the immunosuppressive tumor microenvironment with excellent biocompatibility. The photothermally responsive nano‐heterojunction presents an innovative paradigm for the simultaneous activation of ferroptosis and PANoptosis via combined PDT and PTT, offering new avenues for semiconductor‐based cancer immunotherapy.