Engineering Bioinspired Nanomedicines to Mitigate the Resistance to Cancer Immunotherapy

ConspectusThe current era has witnessed the success of immunotherapy, in particular, immune checkpoint blockade (ICB) therapy, at an unprecedented pace. However, immunotherapy often fails to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex tumor microenvironment (TME) and the occurrence of intrinsic and adaptive immune resistance of tumor cells. In recent years, we have rationally engineered a set of bioinspired stimuli-activatable nanotherapeutics to circumvent cancer immune resistance and potentiate cancer immunotherapy. To prompt the development of nanomedicine-based cancer immunotherapy, in this Account we first introduced the mechanisms of intrinsic and adaptive immune resistance from a tumor cell perspective. We then summarized the bioinspired nanomedicine strategies exploited in our laboratory in the past few years to circumvent both the intrinsic and adaptive immune resistance. These nanoparticles were rationally engineered for highly tumor-specific drug delivery of the immunotherapeutics by responding to the endogenous signals of TME including extracellular/intracellular acidity, overexpressed enzymes, glutathione, and reactive species. These nanoparticles caused the intrinsic immune resistance to migrate by restoring tumor-associated antigen presentation on the surface of tumor cells, repolarizing the tumor-associated macrophages, and eliciting antitumor immunogenicity via the induction of the immunogenetic cell death of tumor cells. Meanwhile, these nanoparticles were also loaded with small molecular or macromolecular immune inhibitors to relieve the inducible expression of the immune checkpoints (e.g., programmed cell death of ligand 1 and indolamine 2,3-dioxygenase 1), thereby relieving the adaptive immune resistance. Overviews of the nanomedicine strategies used to cause the immune resistance to migrate by regulating lactate metabolism and lipid peroxidation were also provided. Furthermore, we suggested rational combination strategies according to diverse cancers to mitigate multiple immune resistance. These tactics can be adopted to perpetuate the cancer immunity cycle for clinical therapy of immune-resistant cancer. It is envisaged that TME-activatable bioinspired nanomedicines to bypass immunosuppressive signaling pathways may broaden the clinical impact of cancer immunotherapy.