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

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.