hMENA isoforms regulate cancer specific Type I IFN signaling and extrinsic mechanisms of resistance to immune checkpoint blockade

The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and when expressed in tumor cells with the epithelial specific hMENA11a isoform, identifies NSCLC patients with prolonged disease free survival (1,2). hMENA11a sustains cell-cell junction integrity in epithelial tumors (3, 4) where its expression is regulated by ESRP, a critical splicing regulator factor lost in epithelial-mesenchymal transition (EMT) (5). Recent evidences have highlighted the interaction between actin cytoskeleton and its related proteins and innate immune proteins, including the viral sensor RIG-I (retinoic acid-inducible gene I). Indeed cytoskeleton regulatory proteins with crucial roles in tumor progression may bind immune proteins, participating to viral mimicry, a process occurring in cancer in sterile conditions with critical effects on tumor progression and resistance to therapy (6). Type I interferons (IFN-Is) are key drivers of inflammation and immunosuppression in chronic infection. Similarly, in cancer, IFN-Is activate multiple mechanisms promoting inflammatory signals but may also initiate feedback suppression in both immune