Sierra Jesus, de León Ugo Avila-Ponce, Padilla-Longoria Pablo
CIMAT, De Jalisco s/n, Gto., 36023, Guanajuato, Mexico.
Schiffer Group, Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Mol Cell Biochem. 2025 Jun;480(6):3735-3747. doi: 10.1007/s11010-025-05205-2. Epub 2025 Jan 19.
Disturbance of epigenetic processes can lead to altered gene function and malignant cellular transformation. In particular, changes in the epigenetic landscape are a central topic in cancer biology. The initiation and progression of cancer are now recognized to involve both epigenetic and genetic alterations. In this paper, we study the epigenetic mechanism (related to the tumor microenvironment) responsible for increasing tumor-associated macrophages that promote the occurrence and metastasis of tumor cells, support tumor angiogenesis, inhibit T-cell-mediated anti-tumor immune response, and lead to tumor progression. We show that the tumor benefits from the macrophages' high degree of plasticity and larger epigenetic basins corresponding to phenotypes that favor cancer development through a process that we call noise-induced polarization. Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt). Our results show that a combination therapy may be necessary to ensure the proper epigenetic stability of macrophages, which otherwise will contribute to cancer progression. On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages' immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington's landscape) as the backbone for our study, which encapsulates the biological information of the system.
表观遗传过程的紊乱会导致基因功能改变和细胞恶性转化。特别是，表观遗传格局的变化是癌症生物学的核心主题。现在人们认识到，癌症的发生和发展涉及表观遗传和基因改变。在本文中，我们研究了（与肿瘤微环境相关的）表观遗传机制，该机制导致肿瘤相关巨噬细胞增多，这些巨噬细胞促进肿瘤细胞的发生和转移，支持肿瘤血管生成，抑制T细胞介导的抗肿瘤免疫反应，并导致肿瘤进展。我们表明，肿瘤通过一个我们称为噪声诱导极化的过程，从巨噬细胞的高度可塑性和与有利于癌症发展的表型相对应的更大表观遗传池中获益。此外，我们提出了一种机制，以促进涉及巨噬细胞的免疫疗法的适当表观遗传稳定性，其中包括p53和APR - 246（依普那肽）。我们的结果表明，可能需要联合治疗来确保巨噬细胞的适当表观遗传稳定性，否则巨噬细胞会促进癌症进展。另一方面，我们得出结论，在TP53突变较少的癌症类型（如结直肠癌）中，巨噬细胞可能保持抗肿瘤状态；在这些情况下，巨噬细胞免疫疗法可能更合适。我们最后提到了表观遗传潜能（沃丁顿格局）作为我们研究基础的相关性，它概括了系统的生物学信息。
