Combined Photothermal and mTOR-Targeted Therapy Overcomes Immune Evasion and Enhances Checkpoint Blockade Efficacy in Metastatic Triple-Negative Breast Cancer.

Triple-negative breast cancer, a representative immune "cold" tumor, resists immune checkpoint blockade (ICB). A promising strategy to overcome this limitation involves combining photothermal therapy (PTT) with ICB. Here, it is demonstrated that while PTT enhances antitumor immunity by inducing immunogenic cell death (ICD), it paradoxically activates the oncogenic mTOR pathway, driving tumor immune evasion. To address this, ASPPR∩A, a mTOR inhibitor-loaded and pH/NIR-II-responsive gold nanocomposite delivering localized hyperthermia and mTOR inhibition, are developed. The nanocomposite selectively targets tumor cells and efficiently converts NIR-II light into hyperthermia upon laser irradiation. In vitro, the nanocomposite-mediated photothermal-mTOR dual-therapy synergistically enhances ICD and MHC-I antigen presentation. In murine TNBC models, this combination significantly amplifies ICD and T-cell infiltration, and synergizes with PD-1 blockade. Notably, this triple-combination regimen effectively eliminates distant metastases via systemic antitumor immune response. The findings reveal the paradoxical role of PTT, establishing a photothermal-targeted-immune combinatorial paradigm for treating metastatic immune "cold" tumors.