Ion-Pairing Therapeutic Agents to Overcome Immune Resistance for Enhancing Type I Near-Infrared Photodynamic Immuno/Chemotherapy.

Photodynamic therapy (PDT) is well-known to induce tumor immunotherapy by immunogenic cell death (ICD). However, oxygen-dependent Type II PDT paradoxically exacerbates hypoxia, driving PD-L1-mediated immune evasion and undermining therapeutic efficacy. Herein, we present an ion-pairing therapeutic agent (IPTA) strategy based on a Type I near-infrared (NIR) anionic photosensitizer and a mitochondrial-targeting cationic inhibitor. The designed ion-pairing therapeutic agent CyR-TL exhibits a dramatically enhanced singlet oxygen quantum yield (∼21.08-fold that of ICG) and excellent superoxide anion (O2-•) generation capability, enabling effective tumor cell suppression under low-power and short-duration NIR irradiation across both normoxic and hypoxic conditions. Meanwhile, CyR-TL plays a role in chemotherapy-mediated suppression of mitochondrial oxidative phosphorylation to downregulate PD-L1, effectively counteracting PDT-induced immune resistance without requiring exogenous checkpoint inhibitors. Synergizing with PDT-triggered immunogenic cell death (ICD), the designed ion-pairing therapeutic agent integrates the hypoxia-tolerable NIR Type I PDT mechanism with PD-L1-downregulating capability for enhancing photodynamic immunotherapy and chemotherapy.