Rewiring Dendritic Cell Immunity: The β-Catenin-TIM-3 Axis as a Target to Improve DC Cancer Vaccines.

The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs-particularly in cross-presenting cDC1s-induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin-TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin-TIM-3 checkpoint axis-alone or together with PD-L1 and other β-catenin-linked receptors-could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies.