三阴性乳腺癌（TNBC）患者经常对化疗产生耐药性，导致复发。鉴于 TNBC 的异质性和生物标志物的缺乏，优化抗肿瘤免疫效应的方法有望克服这种耐药性。在这项研究中，我们重点关注巨噬细胞中的 YTHDF2，一种 N6-甲基腺苷 (m6A) RNA 阅读器蛋白，巨噬细胞是最丰富的肿瘤内免疫细胞之一。通过单细胞测序和离体实验，我们发现 YTHDF2 显着促进巨噬细胞的促肿瘤表型极化，并且与 TNBC 中其他免疫细胞的抗原呈递信号下调密切相关。体外剥夺 YTHDF2 有利于抗肿瘤作用。在 YTHDF2 高巨噬细胞中一致观察到多种转录因子（尤其是 SPI1）的表达，为新策略提供了潜在的治疗靶点。总之，巨噬细胞中的 YTHDF2 似乎可以促进促肿瘤作用，同时抑制免疫活性，表明针对 YTHDF2 或其转录因子的治疗可能是治疗耐药 TNBC 的一种有前景的策略。© 2024 作者。

Patients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.© 2024 The Authors.