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. 2022 Sep 15;13:915094. doi: 10.3389/fimmu.2022.915094

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Copyright © 2022 Zhou, Ni, Liang, Lin, An, He and Zhao

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Strategies reversing PD-1/PDL1 blockade by releasing tumor antigens (A) and enhancing antigen presentation (B). A.Chemotherapy, radiotherapy and oncolytic viruses could promote the immunogenic cell death (ICD), enhancing the liberation of immunogenic neoantigens, thus increasing the antigenicity in tumors resistant to ICB due to the failure of antigen recognition. In addition, some minimally invasive thermal ablation treatments lead to antigens release as well. (B) DNMTi, HDACi, HMTi epigenetically modulate the upregulation of MHC pathway. Stabilization of NF-κB, restoration of IFN signaling and induction of stimulator of interferon genes (STING) also reverse MHC-I downregulation. Besides, stimulation factors including cytokines such as FLT3L (FMS-like tyrosine kinase 3 ligand) and GM-CSF (granulocyte–macrophage colony-stimulating factor), Toll-like receptor (TLR2/TLR4, TLR3, TLR7/TLR8, TLR9) agonists, IDO inhibitors and STAT3 inhibitors could augment the infiltration, activation, and effector function of conventional DCs (cDCs), thus increasing antigen delivery. DC vaccines are also important tools boosting antigen presentation. The picture was created with BioRender.com. ICD, immunogenic cell death; STING, stimulator of interferon genes; FLT3L, FMS-like tyrosine kinase 3 ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; TLR, Toll-like receptor; IDO, indoleamine- (2,3)-dioxygenase; DC, dendritic cell.