Polarization of Tumor-Associated Macrophages by Nanoparticle-Loaded Combined with Immunogenic Cell Death for Cancer Immunotherapy. Wei Baicheng,Pan Jingmei,Yuan Ruiting,Shao Binfen,Wang Yi,Guo Xing,Zhou Shaobing Nano letters The tumor immunosuppressive microenvironment greatly limits the efficacy of immunotherapy. Tumor-associated macrophages (TAMs) are the most abundant immunosuppressive cells in the tumor microenvironment, which can inhibit the tumor after converting it to an M1-like phenotype. In addition, immunogenic cell death (ICD) can increase the amount of T lymphocytes in tumors, activating antineoplastic immunity. Herein, tumor-associated macrophage polarization therapy supplemented with PLGA-DOX (PDOX)-induced ICD is developed for cancer treatment. The nanoparticles/bacteria complex (Ec-PR848) is fabricated for tumor targeting and TAM polarization, and PLGA-R848 (PR848) are attached to the surface of () MG1655 via electrostatic absorption. The toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) and can greatly polarize M2 macrophages to M1 macrophages, while PDOX-induced ICD can also impair the immunosuppression of the tumor microenvironment. This strategy shows that tumor-associated macrophage polarization therapy combined with ICD induced by low-dose chemotherapeutic drugs can commendably enhance the efficacy of immunotherapy. 10.1021/acs.nanolett.1c00209

The loss of RNA N-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8 T cell dysfunction and tumor growth. Dong Lihui,Chen Chuanyuan,Zhang Yawei,Guo Peijin,Wang Zhenghang,Li Jian,Liu Yi,Liu Jun,Chang Renbao,Li Yilin,Liang Guanghao,Lai Weiyi,Sun Mengxue,Dougherty Urszula,Bissonnette Marc B,Wang Hailin,Shen Lin,Xu Meng Michelle,Han Dali Cancer cell Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q TAMs are regulated by an RNA N-methyladenosine (mA) program and modulate tumor-infiltrating CD8 T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an mA methyltransferase Mettl14 drives CD8 T cell differentiation along a dysfunctional trajectory, impairing CD8 T cells to eliminate tumors. Mettl14-deficient C1q TAMs show a decreased mA abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8 T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-mA levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an mA methyltransferase in TAMs promotes CD8 T cell dysfunction and tumor progression. 10.1016/j.ccell.2021.04.016