Photodynamic Modulation of Endoplasmic Reticulum and Mitochondria Network Boosted Cancer Immunotherapy

Abstract Immunogenic cell death (ICD) represents a promising approach for enhancing tumor therapy efficacy by inducing antitumor immune response. However, current ICD inducers often have insufficient endoplasmic reticulum (ER) enrichment and ineffectiveness in tumor immune escape caused by ER‐mitochondria interaction. In this study, a kind of photoactivatable probe, THTTPy‐PTSA, which enables sequential targeting of the ER and mitochondria is developed. THTTPy‐PTSA incorporates p‐Toluenesulfonamide (PTSA) for ER targeting, and upon light irradiation, the tetrahydropyridine group undergoes a photo oxidative dehydrogenation reaction, transforming into a pyridinium group that acts as a mitochondria‐targeting moiety. The results demonstrate that THTTPy‐PTSA exhibits exceptional subcellular translocation from the ER to mitochondria upon light irradiation treatment, subsequently triggers a stronger ER stress response through a cascade‐amplification effect. Importantly, the augmented ER stress leads to substantial therapeutic efficacy in a 4T1 tumor model by eliciting the release of numerous damage‐associated molecular patterns, thereby inducing evident and widespread ICD, consequently enhancing the antitumor immune efficacy. Collectively, the findings emphasize the pivotal role of photodynamic modulation of the ER‐mitochondria network, facilitated by THTTPy‐PTSA with precise spatial and temporal regulation, in effectively bolstering the antitumor immune response. This innovative approach presents a promising alternative for addressing the challenges associated with cancer immunotherapy.