Multifunctional Nanodrug-Mediated Immunotherapy in Microsatellite Stable Colorectal Cancer via Promoting m6A Modification and M1-Like Tumor-Associated Macrophages Polarization

Immunotherapy has made great progress in various solid tumors. However, the "cold" tumor immune microenvironment of microsatellite stable subtype colorectal cancer (MSS-CRC) hinders the effectiveness of immunotherapy. Therefore, reshaping the immunosuppressive microenvironment and initiating efficient antitumor immune responses are critical for immunotherapy of MSS-CRC. According to the analysis of clinical samples, it is found that the levels of fat mass and obesity-associated protein (FTO) and M2-like tumor-associated macrophages (TAMs) infiltration are significantly elevated in CRC tissue, which has driven one to construct a targeted cationic liposome to simultaneously enhance the RNA methylation and inhibit the CD47 immune checkpoint expression of tumor cells in the hope of promoting the M1-like TAMs polarization and phagocytosis. By upregulating the m6A modification of tumor cells, the lactate secretion is decreased to promote the TAMs repolarized into M1-like. Meanwhile, CD47 siRNA codelivered by the cationic liposomes downregulates the expression of immune checkpoint CD47 on the cancer cell surface, which enhances the phagocytic ability of the M1-like TAMs. The combination treatment scheme is expected to provide a new option for treating MSS-CRC, which may also be extended for treating other immunologically "cold" tumors. The si/F@RL nanodrug is developed to enhance the microsatellite stable subtype colorectal cancer therapeutic effect by inhibiting the CD47 expression and amplifying M1-like polarization of tumor-associated macrophages. In vivo studies in orthotopic tumor and liver metastasis models demonstrate that the nanodrugs mediate a strong synergistic anticancer effect, inhibiting tumor growth and metastasis.image (c) 2024 WILEY-VCH GmbH