A NIR‐Light‐Activated and Lysosomal‐Targeted Pt(II) Metallacycle for Highly Potent Evoking of Immunogenic Cell Death that Potentiates Cancer Immunotherapy of Deep‐Seated Tumors

Abstract

AbstractThough platinum (Pt)‐based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep‐seated tumors remains a formidable challenge. Herein, we propose the first example of a near‐infrared (NIR) light‐activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep‐seated tumors via multiple‐regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth‐activated ROS production (~7 mm), accompanied by strong anti‐diffusion and anti‐ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 μM) compared with the clinical ICD inducer‐oxaliplatin (300 μM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8+/CD4+ T cell response and Foxp3+ T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal‐based ICD agents in immunotherapy.