Recent Advances in Stimuli-Responsive Platforms for Cancer Immunotherapy.

Immunotherapy has attracted significant interest because of its tremendous potential in cancer therapy. The recent advances in the identification of cancer-associated neoantigens, chimeric antigen receptor (CAR) T-cell and immune checkpoint blockade (ICB), have revolutionized the field of cancer immunotherapy. Cancer immunotherapeutic agents typically exhibit strong immune activation or inhibition activity, thereby inducing robust biological effect even when administered at a small dosage. However, in most cases, cancer immunotherapeutic targets are not cancer specific. Some of them are also expressed in nonmalignant normal tissues and the undesired release of the cancer immunotherapeutic agents into these normal tissues may lead to severe side effects. Thus, the on-demand release of the cancer immunotherapeutic agents into the target site is critical to achieving efficient antitumor immune responses while minimizing the side effects.In this Account, we introduce the recent progress of our group and others on the development of stimuli-responsive platforms for cancer immunotherapy. Stimuli-responsive platforms have been constructed for on-demand release of payloads in a temporally and spatially controllable manner. First, we give a brief introduction to the endogenous and exogenous stimuli that are employed to trigger the release of cancer immunotherapeutic agents. The chemical design strategies to construct the specific stimuli-responsive delivery systems are highlighted. Moreover, the recently developed representative stimuli-responsive platforms for the delivery of immune checkpoint inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, stimulator of interferon genes (STING) agonists, and near-infrared photoimmunotherapy (NIR-PIT) agents are discussed in detail. Meanwhile, we summarize the general chemical design for constructing stimuli-responsive delivery platforms targeting immune targets at distinct locations. Lastly, the probable issues on the clinical translation of these stimuli-responsive platforms for cancer immunotherapy are outlined. Since we are still on the way of exploring the immune system and optimizing the chemical design of biomaterials, we hope the information in this account can provide some valuable references for the development of optimal cancer immunotherapeutics.