Wnt signaling pathway in cancer immunotherapy

Figure 1. Canonical Wnt/β-catenin signaling pathway. Wnt ligands are secreted into the extracellular matrix upon acylation by PORCN, replacing DKK1 on LRP5/6 on the adjacent cells, binding to LRPs and FZD. DVL1 is subsequently recruited, GSK3β is phosphorylated instead of β-catenin, and the destruction complex consisting of β-cat, APC, Axin, CK1α, and GSK3β dissociates. Consequently, β-catenin is no longer shuttled to the proteasome for degradation. Instead, accumulated β-cat can translocate to nucleus, where it replaces Groucho to bind with TCF/LEF, form a complex with co-activators, including CBP, P300, PYGO, and BCL9, to stimulate Wnt-targeted gene expression and cell proliferation. Figure 2. Wnt/β-cat signaling in vital immuno-oncological components. Activated Wnt/β-cat signaling in cancer cells can deplete DC recruitment by downregulating CCL4 expression, thereby decreasing CXCL9/10 and IL-10 secretion to limit CD8+ T cell infiltration and priming. Wnt-active DCs can also restrain CD8+ T cells, thereby benefiting TREG function and enhancing immunosuppression. The differentiation of CD4+ T cells into TH1 and TH2 can be enforced by β-cat activity. TAMs can interact with Wnt-active cancer cells through IL-1β and Snail, while MDSCs regulate CD8+ T cell infiltration and function. PD-L1 and NKAL on cancer cells are upregulated, ligand-receptor interactions are enhanced, and PDL1-PD1-induced CD8+ T cell exhaustion is triggered to form a non-T cell-inflamed TME.