Engineering Semiconducting Polymeric Nanoagonists Potentiate cGAS‐STING Pathway Activation and Elicit Long Term Memory Against Recurrence in Breast Cancer

Abstract Triple‐negative breast cancer has an immunologically “cold” microenvironment, which leads to resistance to current immunotherapy. The activation of stimulator of interferon genes (STING) pathway has been thought a promising strategy to enhance immunotherapy efficacy. In this study, we adopted a comprehensive strategy that integrates innate immune responses with tumor‐targeting photothermal therapy (PTT) to simultaneously tackle multiple immune‐suppressive mechanisms in breast cancer. This semiconducting polymeric nanoagonists (DPTT‐Mn Lipo NPs) mediated PTT can effectively initiate tumor cell apoptosis and induce ICD, thereby reprogramming the immunosuppressive TME and activating STING. We confirmed the modulation of the TME through the PTT‐mediated ICD effect and the transactivation of the cGAS‐STING pathway in immune cells of the TME due to the released dsDNA via ICD, such as macrophages and DCs. Indeed, DPTT‐Mn Lipo NPs‐mediated PTT promoted M1 polarization of tumor‐associated macrophages, augmented T‐cell infiltration, facilitated dendritic cell (DC) maturation, and regulated type I interferon factor secretion, leading to efficient tumor suppression. Most importantly, the combination of DPTT‐Mn Lipo NPs‐based PTT with a checkpoint blockade therapy (anti‐PD‐1) can elicit long‐term immune memory besides tumor eradication. Collectively, this nano‐system can systemically activate antitumor immunity through STING activation and potentially establish long‐term memory against tumor recurrence.