Modulation of tumor drug sensitivity and inflammatory signaling through CMTM4

Although the association between inflammation and cancer development has been recognized, how inflammation affects the outcomes of immunotherapy and chemotherapy hasn’t yet been well evaluated. In this study, we found that CKLF-like MARVEL transmembrane domain-containing member 4 (CMTM4) was highly expressed in multiple human and murine cancers. Loss of CMTM4 significantly reduced tumor growth and impaired NFB, mTOR, PI3K/Akt pathway activation. Interestingly, we found that CMTM4 can regulate epidermal growth factor (EGF) signaling post-translationally by promoting EGFR recycling and preventing its degradation through Rab proteins. Consequentially, CMTM4 knockout promoted response sensitivity of human tumor cells to EGFR inhibitors. Importantly, CMTM4 knockout tumors stimulated with EGF significantly decreased their production of inflammatory cytokines including G-CSF, leading to decreased recruitment of polymorphonuclear myeloid-derived suppressor cells and thus, a less suppressive tumor-immune-environment. Therapeutically, siRNA-liposome targeting CMTM4 reduced tumor growth in vivo and prolonged animal survival. Furthermore, CMTM4 knockout enhance immune checkpoint blockade or chemotherapy to reduce tumor growth. These data suggest that CMTM4 represents a novel target to inhibit tumor inflammation and improve immune response and drug sensitivity.