FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and largely refractory to current therapies, underscoring the need to uncover the molecular drivers of progression to identify targetable vulnerabilities. In this study, we found that fibronectin type III domain-containing 4 (FNDC4), known for its role in macrophage polarization and metabolic regulation, was elevated in metastatic PDAC cells and correlated with poor patient outcomes. FNDC4 knockdown reduced tumor growth and metastasis in a diverse set of aggressive PDAC models. Mechanistically, FNDC4 enhanced cell cycle and apoptosis regulator 1 (CCAR1) stability, thereby sustaining CCAR1/β-catenin signaling. FNDC4 deficiency led to reduced CCAR1 and β-catenin expression and consequently impaired invasion and colony formation. Moreover, FNDC4 promoted immune evasion by driving macrophage polarization toward a protumorigenic M2 phenotype. FNDC4 loss shifted macrophage polarization toward an antitumor profile and increased CD4+ and CD8+ T-cell infiltration. Together, the effects of FNDC4 targeting resulted in reduced tumor burden, suppression of metastasis, and improved survival in immunocompetent murine PDAC models. Unexpectedly, FNDC4 localized to the nucleus, pointing to potential intranuclear activity. Transcriptomic and functional analyses further identified CCL5 as a critical downstream effector, required for recruiting CCR5+ T cells and mediating the immune effects of FNDC4 inhibition. Upstream, BHLHE40 directly activated FNDC4 transcription, which was stimulated by induction of epithelial-mesenchymal transition. Importantly, combining FNDC4 inhibition with claudin 18.2 chimeric antigen receptor T cells or chemotherapy resulted in enhanced tumor control compared with monotherapy. Together, these findings underscore the role of FNDC4 in promoting PDAC progression and the potential of FNDC4 as a target for innovative multimodal treatment strategies. SIGNIFICANCE: FNDC4 is a key driver of pancreatic cancer invasiveness and immunosuppression that can be targeted to reprogram the pancreatic tumor microenvironment and suppress tumor metastasis, offering a promising therapeutic strategy.