Remodeling TME via feedback-driven photothermal-ferroptosis-immune cascade

Triple-negative breast cancer (TNBC) is recognized as one of the most aggressive breast cancer subtypes, with poor responsiveness to current immunotherapies primarily due to its strongly immunosuppressive tumor microenvironment (TME). Here, we report a multifunctional nanoplatform, AIF NPs that integrates near-infrared (808 nm) photothermal therapy (PTT), ferroptosis induction, and immunosuppressive axis blockade into a feedback-amplified therapeutic system. The silicon-based photothermal agent IR1024 demonstrates an exceptionally high photothermal conversion efficiency of 93.4%, enabling efficient PTT under clinically relevant irradiation. Ferroptosis-induced lipid peroxidation downregulates HSP90, attenuating thermo-resistance; PTT-generated heat accelerates fatty acid oxidation and lipid peroxidation, further amplifying ferroptosis. The resulting immunogenic cell death (ICD) promotes dendritic cell maturation and CD8⁺ T cell infiltration, while AB928 alleviates adenosine-mediated immunosuppression, allowing ICD-driven immunity to be sustained. This immune activation enhances IFN-γ production, which cooperates with arachidonic acid (AA) to downregulate SLC7A11 and further reinforce ferroptosis, thus completing a self-reinforcing PTT-ferroptosis-immunity loop. Experimental results demonstrate that AIF NPs effectively rewires immunologically "cold" TNBC into a responsive "hot" phenotype, achieving over 90% tumor growth inhibition in a 4T1 murine model with minimal systemic toxicity. These findings highlight how feedback-driven coordination of cell death and immunity can be strategically leveraged to address therapeutic bottlenecks in TNBC.