Reversing Immunosuppression in Hypoxic and Immune‐Cold Tumors with Ultrathin Oxygen Self‐Supplementing Polymer Nanosheets under Near Infrared Light Irradiation

Abstract Solid tumors are characterized by a hypoxic and immunologically “cold” microenvironment that dramatically limits the therapeutic outcomes of immunotherapy. Thus, strategies and materials that are capable of reversing immunosuppression in immune‐cold tumors are highly desired. Herein, it is reported that oxygen (O 2 ) self‐supplementing conjugated microporous polymer nanosheets can be utilized to elicit a robust antitumor T cell immune response in the hypoxic and immunosuppressive tumor microenvironment. The ultrathin nanosheets can generate O 2 through the water splitting reaction and produce massive reactive oxygen species (ROS) under near infrared light irradiation. Meanwhile, the unique photothermal property of the conjugated polymer nanosheets generates hyperthermia under irradiation. Consequently, they are able to maximize the immunogenic cell death (ICD) performance by inducing adequate damage‐related molecular patterns in hypoxic tumors. Other than fostering T cell infiltration by the elicited ICD, the loaded indoleamine 2,3‐dioxygenase in nanosheets can reverse the immunosuppression and empower ICD effect for efficient T cells priming. In vivo experiments conclusively prove that the designed polymer nanosheets exhibit great potential for tumor eradication, metastasis prevention, as well as long‐term survival. Such a photocatalytic platform opens up new paths for reversing immunosuppression in immune‐cold tumors and broadens the application of polymer‐based nanosheets for cancer therapy.