Enhancing anti-tumor immunity through TIGIT blockade and tumor-directed targeting in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to immune checkpoint blockade, driven by a dense stroma, low immunogenicity, and an immunosuppressive tumor microenvironment. T cell immunoreceptor with Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed on tumor-infiltrating lymphocytes and contributes to immune dysfunction in PDAC through its interaction with PVR. To selectively modulate the TIGIT axis within the tumor microenvironment, we developed a bispecific antibody (chi2B5×4F11) that targets TIGIT while anchoring to CUB domain-containing protein 1 (CDCP1), thereby enabling spatially confined immune activation in CDCP1-positive tumor niches. Functional characterization using in vitro NK-92 cell assays and in vivo studies using a humanized mouse model engrafted with CDCP1⁺ PANC-1 cells demonstrated the efficacy of these antibodies. Parental chi4F11 effectively blocked the TIGIT-PVR axis, restoring AKT-FOXO1 signaling without altering CD226 expression. Chi2B5×4F11 further enhanced NK-92 cell-mediated cytotoxicity and induced the release of pro-inflammatory cytokines in vitro. In vivo, treatment with chi2B5×4F11 reduced the proportion of TIGIT⁺ circulating immune subsets within the CD226⁺ compartment, suggesting functional restoration of co-stimulatory signaling. These findings highlight TIGIT as a crucial therapeutic target and suggest a strategy to overcome the immune resistance of pancreatic cancer.