β-Catenin inhibition shapes tumor immunity and synergizes with immunotherapy in colorectal cancer.

In colorectal cancer, Wnt/β-catenin signaling is often aberrantly activated and associated with a T-cell-excluded phenotype which is a major obstacle for many immunotherapies. However, the effects of Wnt/β-catenin inhibition on tumor immunity and immunotherapy remain to be elucidated. In syngeneic mouse models of colorectal cancer, β-catenin/TCF inhibitor iCRT14 potently enhanced the infiltration of T and NK cells, without influencing their proliferation or the infiltration of most myeloid populations. Mechanistically, β-catenin inhibition upregulated while its overexpression suppressed the expression of T/NK cell-recruiting CXCR3 chemokines CXCL9/10/11 in both mouse and human colorectal cancer cells. Furthermore, iCRT14 treatment synergized with tumor vaccines or Treg cell ablation to achieve a complete inhibition of tumor growth in syngeneic models of CT26-OVA and MC38-S33Y.β-cat, respectively. Taken together, our work reveals that β-catenin inhibition shifts colorectal tumor microenvironment into a T-cell-inflamed phenotype and potentiates the efficacy of other immunotherapeutic strategies for colorectal cancer.