Methionine enkephalin inhibits colorectal cancer by remodeling the immune status of the tumor microenvironment

There is evidence that methionine enkephalin (MENK), an opioid peptide, promotes anti-tumor immune re-sponses. In this study, the effect of MENK on colorectal cancer (CRC) and its mechanisms of action were examined in vivo. The intraperitoneal administration of 20 mg/kg MENK effectively inhibited MC38 subcu-taneous colorectal tumor growth in mice. MENK inhibited tumor progression by increasing the immunogenicity and recognition of MC38 cells. MENK down-regulated the oncogene Kras and anti-apoptotic Bclxl and Bcl2, suppressed Il1b, Il6, iNOS, and Arg1 (encoding inflammatory cytokines), and increased Il17a and Il10 levels. MENK promoted a tumor suppressive state by decreasing the immune checkpoints Pd-1, Pd-l1, Lag3, Flgl1, and 2b4 in CRC. MENK also altered the immune status of the tumor immune microenvironment (TIME). It increased the infiltration of M1-type macrophages, CD8+T cells, and CD4(+)T cells and decreased the proportions of G-MDSCs, M-MDSCs, and M2-type macrophages. MENK accelerated CD4(+)TEM and CD8(+)TEM cell activation in the TIME and up-regulated IFN-gamma, TNF-alpha, and IL-17A in CD4(+)T cells and Granzyme B in CD8(+)T cells. In addition, analyses of PD-1 and PD-L1 expression indicated that MENK promoted the anti-tumor immune response medi-ated by effector T cells. Finally, OGFr was up-regulated at the protein and mRNA levels by MENK, and the inhibitory effects of MENK on tumor growth were blocked by NTX, a specific blocker of OGFr. These finding indicate that MENK remodels the TIME in CRC to inhibit tumor progression by binding to OGFr. MENK is a potential therapeutic agent for CRC, especially for improving the efficacy of immunotherapy.

Automated summary

Evidence suggests that methionine enkephalin (MENK), an opioid peptide, can inhibit the progression of colorectal cancer by remodeling the tumor immune microenvironment and increasing the immunogenicity of cancer cells. MENK down-regulates oncogenes and inflammatory cytokines while up-regulating immune mediators, leading to enhanced anti-tumor immune responses. It also promotes the activation of effector T cells and reduces the expression of immune checkpoints. Furthermore, MENK binds to the Mu opioid receptor (OGFr), and blocking OGFr activity reverses the inhibitory effects of MENK on tumor growth.