Fig. 3
From: Targeting the epigenome to reinvigorate T cells for cancer immunotherapy
Targeting the epigenetic regulation of extrinsic drivers of T cell exhaustion via epidrugs and CRISPR-based epigenome editing. a Epigenetic modulation of chemokines could direct the formation and coordination of spatial immune contexture. TN and DCs migrate into the TdLN via CCR7-CCL19/21 chemokine axis as part of the cancer-immunity cycle, together with CXCL9/10-dependent trafficking of TEFF and TPEX cells from the TdLN to the TIME. Within TdLN CCL5 gradient mediates homing of TN cells to the T cell zone (TCZ) in the medulla for priming by antigen presenting cells (APCs), while similar APC niches exist in the stromal compartments of the TIME, crucial to ICI-elicited antitumor immunity. Within the TIME tertiary lymphoid structures (TLSs) consist of follicular dendritic cells (FDCs), B cells, follicular T helper (TFH) cells and CXCL13+ dysfunctional T cells. This subset is speculated to mediate the formation of TLSs via releasing CXCL13, which could be enhanced by epigenetic therapies. b Epigenetic upregulation of tumor immunogenicity could be achieved via increased expression of endogenous retroviruses (ERVs) and their transcription to produce double-strand RNAs (dsRNAs), which are sensed by pattern recognition receptors such as the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING (stimulator of interferon genes) pathways, eventually resulting in upregulation of antigen processing and presentation machineries (AgPPM) and release of type I interferon. c Epigenetic reprogramming of immunosuppressive cells in the TIME and the immune macroenvironment could revitalize antitumor immunity. d Level of extracellular metabolites in the TIME could impact histone modifications (Kla, lysine lactylation; Kme, lysine methylation; Kac, lysine acetylation) through providing cofactors and donor groups to epigenetic enzymes. e Epigenetic reprogramming mediates the microbiomic modulation of anticancer immunity. CAF cancer-associated fibroblast, CCL19 C–C motif chemokine ligand 19, CCR7 C–C motif chemokine receptor 7, EPC erythroid progenitor cells, mregDC mature DC enriched in immunoregulatory molecules, TAM tumor-associated macrophage, acetyl-CoA acetyl coenzyme A, TN naive T cells, TPEX precursor exhausted T cells, TCZ T cell zone, SAM S-adenosylmethionine, HIF-1α hypoxia-inducible factor 1-alpha, CXCL9/10 C-X-C motif chemokine ligand 9/10