Fighting Immune Cold and Reprogramming Immunosuppressive Tumor Microenvironment with Red Blood Cell Membrane-Camouflaged Nanobullets

Nanomedicine, acting as the magic bullet, is capable of combining immunotherapy with other treatments to reverse a cold tumor (immune depletion) into a hot tumor. However, how to comprehensively inhibit the immunosuppressive tumor microenvironment (TME) remains a major challenge for immunotherapy to achieve the maximum benefits. Thus, a strategy that can simultaneously increase the recruitment of tumor infiltrating lymphocytes (TILs) and comprehensively reprogram the immunosuppressive TME is still urgently needed. Herein, a thermal-sensitive nitric oxide (NO) donor S-nitrosothiols (SNO)-pendant copolymer (poly(acrylamide-co-acrylonitrile-co-vinylimidazole)-SNO copolymer, PAAV-SNO) with upper critical solution temperature (UCST) was synthesized and employed to fabricate an erythrocyte membrane-camouflaged nanobullet for codelivery of NIR II photothermal agent IR1061 and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan (1-MT). This multifunctional nanobullet possessed long circulation in vivo, enhanced accumulation at the tumor site, and therapeutics-controlled release by NIR II laser, thereby it could avoid unspecific drug leakage while enhancing biosecurity. More importantly, the immunogenic cell death (ICD) induced by local hyperthermia from photothermal therapy (PTT) could be conducive for the increased recruitment of CD8+ cytotoxic T lymphocytes (CTLs) at the tumor site. Furthermore, through interfering in the IDO-1 activity by 1-MT and normalizing the tumor vessels by in situ generated NO, the immunosuppressive TME was comprehensively reprogrammed toward an immunostimulatory phenotype, achieving the excellent therapeutic efficacy against both primary breast cancer and metastases. Collectively, this multifunctional nanobullet described in this study developed an effective and promising strategy to comprehensively reprogram suppressive TME and treat "immune cold"tumors.