Innate Immune Activation with Multifunctional Nanoparticles for Cancer Immunotherapy.

Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers by leveraging the immune system to combat malignancies. However, its efficacy is limited by the immunosuppressive tumor microenvironment and other regulatory mechanisms of the immune system. Innate immune modulators (IIMs) provide potent immune activation to complement adaptive immune responses and help overcome resistance to ICB. This minireview provides an overview of IIMs and their roles in antitumor immune responses and summarizes recent advances in developing nanotechnology to enhance the delivery of IIMs to tumors for potentiating cancer immunotherapy and mitigating systemic toxicity. We discuss innovative nanoparticle platforms for the delivery of IIMs targeting the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, the toll-like receptor pathway, and the retinoic acid-inducible gene I-like receptor pathway. We review the preliminary clinical readouts of representative IIM nanoptherapeutics and highlight the development of multifunctional nanoparticles for combination treatments of IIMs with conventional treatment mdoalities such as chemotherapy, radiotherapy, photodynmic therapy, and tumor antigens. Finally, we summarize the lessons learned from the existing systems, the challenges in the field, and future perspectives for this exciting field of nanotherapeutics for cancer immunotherapy.