Biodegradable Nanomissile Targeting the NKG2D/NKG2DL Axis Boosts Photo‐Immunotherapy by T Cell plus NK Cell Attack

ABSTRACT Downregulation of major histocompatibility complex class I (MHC‐I) molecules on tumor cells contributes to an immunosuppressive tumor microenvironment (ITM) by impairing immune recognition via the NKG2D receptor. In this study, we developed a photosensitive, biodegradable nanomissile (PCHM) that mimics natural killer (NK) cell membranes to enhance photo‐immunotherapy through coordinated activation of T cells and NK cells. PCHM precisely targets tumor tissues and generates a self‐sustained supply of H 2 O 2 and O 2 , serving as an internal fuel source to amplify photodynamic therapy (PDT). The resulting oxidative stress activates the heat shock protein pathway, upregulating MHC‐I expression and promoting antigen presentation through the NKG2D/NKG2DL axis. This triggers a synergistic immune response involving cytotoxic T lymphocytes (CTLs) and NK cells. In addition to inducing immunogenic cell death and cell‐membrane immunity, PCHM facilitates remodeling of the ITM. It elicits a robust and durable antitumor immune response capable of eradicating both primary and metastatic tumors. Furthermore, combining PCHM with PD‐L1 blockade enhances therapeutic efficacy and prolongs survival. Overall, this work demonstrates the potential of targeting the NKG2D/NKG2DL axis to precisely activate immune responses within tumors, offering an effective strategy to boost PDT and photo‐immunotherapy.