肿瘤细胞治疗研究
英文原题：KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer.
这些发现表明KRAS驱动的m6A重塑是CRC免疫抑制的关键机制，并突显METTL3作为有前景的治疗靶点。
KRAS突变存在于约40%的结直肠癌（CRC）中，与免疫抑制性肿瘤微环境密切相关，其特征为免疫浸润受限和对免疫治疗反应不佳。在此，我们发现KRAS突变重塑N6-甲基腺苷（m6A）表观转录组以促进免疫逃逸。甲基化RNA免疫沉淀测序显示，KRAS突变细胞在CD73 mRNA上表现出增加的m6A沉积，通过IGF2BP3增强其稳定性。TEAD4依赖性地招募METTL3甲基转移酶复合物诱导了m6A修饰，确定TEAD4为m6A沉积的空间调控因子。在功能上，在KRAS突变同系肿瘤中敲低METTL3可抑制肿瘤生长，并通过以CD73依赖的方式增加CD8 T细胞和NK细胞浸润来恢复抗肿瘤免疫。此外，抑制METTL3与抗PD-1治疗和CD73抑制剂协同作用，减少肿瘤负荷。总之，这些发现表明KRAS驱动的m6A重塑是CRC免疫抑制的关键机制，并突出METTL3作为有前景的治疗靶点。
KRAS mutations, present in about 40% of colorectal cancers (CRCs), are strongly associated with an immunosuppressive tumor microenvironment characterized by restricted immune infiltration and poor responses to immunotherapy. Here, we found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion. Methylated RNA immunoprecipitation sequencing revealed that KRAS-mutant cells exhibit increased m6A deposition on CD73 mRNA, enhancing its stability through IGF2BP3. TEAD4-dependent recruitment of the METTL3 methyltransferase complex induced the m6A modification, identifying TEAD4 as a spatial regulator of m6A deposition. Functionally, METTL3 knockdown in KRAS-mutant syngeneic tumors suppressed tumor growth and restored antitumor immunity by increasing CD8 T-cell and NK-cell infiltration in a CD73-dependent manner. Moreover, METTL3 inhibition synergized with anti-PD-1 therapy and a CD73 inhibitor to reduce tumor burden. Together, these findings demonstrate that KRAS-driven m6A remodeling is a key mechanism of immune suppression in CRC and highlight METTL3 as a promising therapeutic target.
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