Hsiao Yi-Jing, Hsieh Min-Shu, Chang Gee-Chen, Hsu Yin-Chen, Wang Chia-Yu, Chen Yan-Ming, Chen Yi-Ling, Yang Pan-Chyr, Yu Sung-Liang
Department of Clinical and Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
Cell Death Dis. 2025 Jan 22;16(1):38. doi: 10.1038/s41419-025-07346-0.
The spatial role of M1 and M2 tumor-associated macrophages (M1/M2 TAMs) in precision medicine remains unclear. EGFR and TP53 are among the most frequently mutated genes in lung adenocarcinoma. We characterized the mutation status and density of M1/M2 TAMs within tumor islets and stroma in 117 lung adenocarcinomas using next-generation sequencing and immunohistochemistry, respectively. Stromal M1 TAMs were positively correlated with disease progression and smoking history. In contrast, islet M1/M2 TAMs were predominantly found in tumors with wild-type TP53 (wtp53) but not associated with EGFR status. The presence of wtp53 was associated with the spatial distribution of M1/M2 TAMs in tumor islets and stroma. Additionally, dominance of islet M1 TAMs and M1-signature were significantly associated with improved survival in patients with wtp53 lung adenocarcinoma, unlike in those with mutant TP53. Conditioned medium from M1 macrophages (M1 CM) induced apoptosis in wtp53 cells through increased p53 accumulation. We found that interferons in M1 CM activate JAK1/TYK2 via IFNARs, leading to enhanced STAT1 expression and Y701 phosphorylation. This activation facilitates p53-STAT1 interactions, reduces the interaction between p53 and MDM2, and subsequently decreases p53 ubiquitination. M1 CM inhibited tumorigenesis, and silencing p53 reduced the anti-tumor efficacy of polyinosinic:polycytidylic acid (poly I:C) in vivo. Furthermore, higher M1-signature was significantly associated with better responses and survival following anti-PD1 treatment in wtp53 melanomas. IFNs/STAT1/p53 signaling was critical for the anti-tumor activity of M1 macrophages. These findings suggest that p53 modulates the spatial balance of M1/M2 TAMs, and the tumoricidal effects of M1 TAMs depend on p53 status. Thus, p53 companion diagnostics could facilitate the development of M1-oriented therapies, which may be particularly beneficial for wtp53 patients when combined with immunotherapy.
M1和M2肿瘤相关巨噬细胞（M1/M2 TAMs）在精准医学中的空间作用尚不清楚。表皮生长因子受体（EGFR）和TP53是肺腺癌中最常发生突变的基因。我们分别使用二代测序和免疫组化方法，对117例肺腺癌肿瘤岛和基质内M1/M2 TAMs的突变状态和密度进行了表征。基质M1 TAMs与疾病进展和吸烟史呈正相关。相比之下，肿瘤岛M1/M2 TAMs主要见于TP53野生型（wtp53）肿瘤，与EGFR状态无关。wtp53的存在与肿瘤岛和基质中M1/M2 TAMs的空间分布有关。此外，与携带TP53突变的患者不同，肿瘤岛M1 TAMs的优势和M1特征与wtp53肺腺癌患者的生存改善显著相关。M1巨噬细胞条件培养基（M1 CM）通过增加p53积累诱导wtp53细胞凋亡。我们发现，M1 CM中的干扰素通过干扰素α/β受体（IFNARs）激活JAK1/TYK2，导致STAT1表达增强和Y701磷酸化。这种激活促进了p53-STAT1相互作用，减少了p53与MDM2之间的相互作用，随后降低了p53泛素化。M1 CM抑制肿瘤发生，而p53沉默降低了聚肌苷酸:聚胞苷酸（poly I:C）在体内的抗肿瘤疗效。此外，较高的M1特征与wtp53黑色素瘤患者接受抗PD1治疗后的更好反应和生存显著相关。干扰素/STAT1/p53信号传导对M1巨噬细胞的抗肿瘤活性至关重要。这些发现表明，p53调节M1/M2 TAMs的空间平衡，M1 TAMs的杀肿瘤作用取决于p53状态。因此，p53伴随诊断可能有助于开发以M1为导向的疗法，当与免疫疗法联合使用时，这可能对wtp53患者特别有益。
