Neutralizing tumor-promoting inflammation with polypeptide-dexamethasone conjugate for microenvironment modulation and colorectal cancer therapy

Tumor is known as “a wound that does not heal”. Tumor-promoting inflammation plays a crucial role in carcinogenesis, tumor progression, tumor metastasis, as well as chemotherapy resistance. Therefore, reducing tumor-promoting inflammation may be a key aspect in targeting the tumor microenvironment for cancer therapy. Dexamethasone (DEX), a commercial drug in the treatment of many different inflammatory diseases, can effectively inhibit the release of substances causing inflammation. However, as a corticosteroid medication, direct use of DEX results in many severe side effects. In this study, a redox and pH dual sensitive polypeptide-DEX conjugate (L–SS–DEX) was synthesized, and the L–SS–DEX dramatically increased the tumoral accumulation of DEX in murine colorectal cancer model (CT26) compared to free DEX. Importantly, at equal dose (10 mg/kg), L–SS–DEX showed superior antitumor activity over free DEX: 86% tumor suppression rate of L–SS–DEX treatment group compared to 49% of free DEX treatment group. Further analysis of the tumor tissues showed that cyclooxygenase-2 (COX-2) and α-smooth muscle actin (α-SMA) were significantly reduced after the L–SS–DEX treatment compared with control groups. In addition, the immunosuppressive microenvironment of the CT26 tumor was effectively relieved after L–SS–DEX treatment, characterized by increased CD8+ T cell infiltration, increased ratio of M1 over M2 macrophages, as well as markedly decrease in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The above results suggest that anti-inflammatory drugs hold great potential in modulating the tumor microenvironment when delivered properly, and can also result in significant tumor inhibition effects. Since dramatic amounts of anti-inflammatory drugs have been used in clinic, our results may provide improved tumor therapy options of using anti-inflammatory drugs for cancer therapy.