Unlocking the Power of Photothermal Agents: A Universal Platform for Smart Immune NIR‐Agonists for Precise Cancer Therapy

Abstract Selective ablation of tumor cells allows safe eradication, thereby minimizing off‐target damage, while specifically inducing immunogenic cell death (ICD) rather than commonly non‐immunogenic apoptosis of tumor cells enables activation of anti‐tumor immune response against residual cancer cells, including metastatic lesions. Herein, we present a general strategy leveraging a novel photothermal agent (PTA) that concomitantly enables precise tumor killing and activation of anti‐tumor immunity. The unique PTA scaffold exhibits unexpected inherent endoplasmic reticulum (ER)‐targeting capability and potent near‐infrared (NIR) photothermal activity, inducing NIR‐controlled immunogenic pyroptosis in various tumor cell lines via targeting ER stress in an oxygen‐independent manner. Moreover, both ER‐targeting and NIR‐activity of our scaffold can be modulated on demand by chemical caging/uncaging, allowing quick activation with diverse biological and bioorthogonal molecular triggers. The potency of this universal platform is demonstrated via its application to develop a membrane protein‐activatable NIR‐agonist that selectively activates ICD in tumor sites while priming anti‐tumor immunity, minimizing off‐target effects and enhancing efficacy against mouse breast tumors. This versatile approach could lead to customization of various personalized and effective immune NIR‐agonists for specific photoimmunotherapy applicable to diverse solid tumors.