Nano-, micro-, and macroscale drug delivery systems for cancer immunotherapy.

Immunotherapy is moving to the frontier of cancer treatment. Drug delivery systems (DDSs) have greatly advanced the development of cancer immunotherapeutic regimen and combination treatment. DDSs can spatiotemporally present tumor antigens, drugs, immunostimulatory molecules, or adjuvants, thus enabling the modulation of immune cells including dendritic cells (DCs) or T-cells directly in vivo and thereby provoking robust antitumor immune responses. Cancer vaccines, immune checkpoint blockade, and adoptive cell transfer have shown promising therapeutic efficiency in clinic, and the incorporation of DDSs may further increase antitumor efficiency while decreasing adverse side effects. This review focuses on the use of nano-, micro-, and macroscale DDSs for co-delivery of different immunostimulatory factors to reprogram the immune system to combat cancer. Regarding to nanoparticle-based DDSs, we emphasize the nanoparticle-based tumor immune environment modulation or as an addition to gene therapy, photodynamic therapy, or photothermal therapy. For microparticle or capsule-based DDSs, an overview of the carrier type, fabrication approach, and co-delivery of tumor vaccines and adjuvants is introduced. Finally, macroscale DDSs including hydrogels and scaffolds are also included and their role in personalized vaccine delivery and adoptive cell transfer therapy are described. Perspective and clinical translation of DDS-based cancer immunotherapy is also discussed. We believe that DDSs hold great potential in advancing the fundamental research and clinical translation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Immunotherapy is moving to the frontier of cancer treatment. Drug delivery systems (DDSs) have greatly advanced the development of cancer immunotherapeutic regimen and combination treatment. In this comprehensive review we focus on the use of nano-, micro- and macroscale DDSs for co-delivery of different immunostimulatory factors to re-program the immune system to combat cancer. We also propose the perspective on the development of next generation DDSs-based cancer immunotherapy. This review indicates that DDSs can augment the antitumor T-cell immunity and hold great potential in advancing the fundamental research and clinical translation of cancer immunotherapy, by simultaneous delivery of dual or multiple immunostimulatory drugs.