Introduction: Tumor-associated macrophages (TAMs) are a functionally heterogeneous population within the tumor microenvironments, exhibiting both anti-tumor and pro-tumor functions. Pro-tumorigenic TAMs can derive from peripheral monocytes or tissue-resident macrophages (TRMs). However, the epigenetic mechanisms driving the differentiation of these distinct cellular sources into specific TAM subtypes remain unclear. Objectives: Here, we sought to define the epigenetic mechanisms that drive the divergent differentiation of monocyte and TRM-derived TAMs. Through a pan-cancer analysis, we map the regulatory cascade, from cis-regulatory elements and key transcription factors to the release of RNA Polymerase II (Pol II) pausing, that specifies TAM heterogeneity. Methods: We performed single-cell epigenetic profiling of macrophages derived from various human cancers, precancerous lesions, and healthy adult and fetal tissues using publicly available datasets, coupled with single-cell multi-omics integration. Key findings were validated through multi-omics analysis of mouse bone marrow-derived macrophage and CRISPR-based functional assays using in vitro human cell culture models.
Results: We delineated the distinct epigenetic developmental trajectories by which peripheral monocytes and TRMs give rise to SPP1+ and C1QC + TAM, respectively. Along the monocyte-to-SPP1+ TAM trajectories, we identified PPARG, NFAT5 and MECP2 as pivotal regulators that promote pro-tumorigenic polarization. Conversely, the differentiation of TRMs to C1QC + TAMs was associated with regulators MAF, HES1 and PRDM1. Furthermore, we discovered a core transcriptional signature regulated by SPP1+ TAM-specific super-enhancers that is significantly associated with poor prognosis across 18 cancer types. Mechanistically, we demonstrated that these enhancers, such as HIPK2 enhancers, establish the protumorigenic TAM state primarily by modulating Pol II pausing rather than by altering promoter accessibility of their target genes. Conclusion: Our work delineates the epigenetic and transcriptional circuitry that establishes TAM heterogeneity as potential therapeutic levers to enhance cancer immunotherapy. (c) 2026 The Author(s). Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
[1]Tianjin Med Univ Canc Inst & Hosp, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Key Lab Breast Canc Prevent & Therapy, State Key Lab Expt Hematol,Minist Educ,Sch Basic M, Tianjin 300070, Peoples R China.
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