Activating Iterative Revolutions of the Cancer‐Immunity Cycle in Hypoxic Tumors with a Smart Nano‐Regulator

Abstract The activation of sequential events in the cancer‐immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off‐target adverse effects of nonselective immunomodulators, persist. In this study, a tumor‐selective nano‐regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self‐assembling system formed by linking a Type‐I photosensitizer to polyethylene glycol through a hypoxia‐sensitive azo bond. Benefiting from the Type‐I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near‐infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T‐lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD‐L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune‐promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.