Whole glucan particles enhance immune modulation in combination with TIGIT checkpoint blockade through Dectin-1 activation.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint blocking antibodies have been shown to be an immune checkpoint blocking (ICB) therapy for cancer patients. However, the anti-tumor effect of blocking TIGIT alone is limited. Whole glucan particles (WGP) are an immune adjuvant that stimulates both innate and adaptive immune responses. In this study, we evaluated WGP in combination with an anti-TIGIT antibody in two models, including LLC lung cancer cell line and 4 T1 breast cancer cell line. Across models, the combination reduced tumor burden and prolonged survival versus either monotherapy. Immune profiling showed increased intratumoral CD8 T and NK cells, macrophage polarization toward an M1-like phenotype, and reductions in MDSCs and Tregs, accompanied by higher pro-inflammatory cytokines and elevated serum IgM/IgA/IgG. In LLC tumors, combination therapy increased Dectin-1/Syk/NF-κB signaling and selectively enhanced MDSC apoptosis with concomitant decreases in Arg-1, iNOS, IL-10, and TGF-β. Crucially, in Dectin-1 knockout mice the combination's benefits on tumor control and MDSC reduction were abolished, providing genetic evidence that WGP's adjuvant effect is Dectin-1 dependent. While the detailed signaling and apoptosis analyses were performed in LLC, the 4 T1 cohort reproduced the antitumor efficacy and immune-activation signatures, supporting generalizability. These results indicated that WGP augments TIGIT blockade through Dectin-1 mediated myeloid reprogramming and coordinated innate adaptive activation, and they supported β-glucan based innate priming as a rational partner for TIGIT and potentially other T-cell-directed checkpoint inhibitors.