DNA repair kinase PRKDC helps liver cancer hide from macrophage attack

Hepatocellular carcinoma, the most common form of primary liver cancer, remains one of the deadliest malignancies in the world, and one of the central reasons is that tumors in the liver are exceptionally good at hiding from the immune system. A new study published in Cancer Immunology, Immunotherapy points to an unexpected culprit in this process: PRKDC, a gene long known for its role in repairing broken DNA, appears to also act as an orchestrator of immune evasion. According to the research team led by Yunyong Wang, Wenpeng Pang, and colleagues in Guangxi, China, PRKDC promotes liver tumor progression by reprogramming the tumor microenvironment, specifically by pushing tumor-associated macrophages toward a tumor-friendly M2-like state through the CSF1/CSF1R signaling pathway.

PRKDC, formally known as the protein kinase, DNA-activated, catalytic polypeptide, encodes the catalytic subunit of the DNA-dependent protein kinase, a molecular machine central to non-homologous end joining, the cellular pathway that stitches double-strand DNA breaks back together. Because of this role, PRKDC has traditionally been studied in the context of genome stability, radiation sensitivity, and lymphocyte development. Yet accumulating evidence has implicated PRKDC in tumor progression across several cancer types, and the new study set out to determine whether the gene also shapes the tumor microenvironment in hepatocellular carcinoma, where tumor-associated macrophages are abundant and tend to adopt an immunosuppressive phenotype.

To test this, the researchers engineered mouse Hepa1-6 liver cancer cells that overexpressed PRKDC and implanted them into mice using both subcutaneous and orthotopic models, the latter recreating tumors within the liver itself. The results were clear: PRKDC overexpression enhanced malignant behaviors in vitro, including proliferation and other hallmarks of aggressive cancer, and accelerated tumor growth in vivo. This established PRKDC not merely as a passive correlate of tumor aggressiveness but as a driver of malignant phenotypes in hepatocellular carcinoma.

The next question was how a DNA repair kinase could exert such broad influence over tumor behavior. Using Olink proteomics, RNA sequencing, quantitative PCR, ELISA, and immunohistochemistry, the team found that PRKDC upregulated CSF1, also known as colony-stimulating factor 1, a secreted cytokine that acts as a key growth and differentiation factor for macrophages. Database analyses further supported CSF1R, the CSF1 receptor, as the primary receptor through which CSF1 signals, and single-cell analysis showed that CSF1R was enriched specifically in tumor-associated macrophages within the tumor microenvironment.

This finding reframed the biology of the tumor microenvironment in hepatocellular carcinoma. Rather than acting solely through intrinsic cancer cell pathways, PRKDC appeared to function as a signaling hub that recruits and reprograms immune cells. By secreting CSF1, PRKDC-overexpressing tumor cells could engage CSF1R on macrophages, nudging them toward an M2-like polarization state. M2 macrophages are known for promoting tissue repair and wound healing, but in the context of cancer they suppress antitumor immunity, support angiogenesis, and facilitate metastasis, making them one of the most treacherous components of the tumor microenvironment.

To validate this mechanism, the researchers performed CSF1R knockdown in mouse RAW264.7 macrophages, which reduced the expression of M2 markers induced by IL-4, a cytokine that normally drives M2 polarization. This demonstrated that CSF1R signaling is required for the M2 program in these macrophages. Immunohistochemistry, co-culture experiments, and flow cytometry then showed increased expression of M2-like tumor-associated macrophage markers in tumors overexpressing PRKDC, confirming that the PRKDC-CSF1 axis reshapes macrophage identity within the tumor microenvironment in living systems, not just in isolated cells.

Perhaps the most striking finding came from macrophage phagocytosis assays. Macrophages are professional phagocytes, capable of engulfing and digesting abnormal cells, including cancer cells that display eat-me signals. The study found that PRKDC-mediated CSF1 upregulation was associated with increased resistance of hepatocellular carcinoma cells to macrophage phagocytosis. In other words, by pushing macrophages toward an M2-like state, PRKDC-overexpressing tumor cells effectively disarmed the very immune cells that should be eliminating them, converting macrophages from attackers into supporters of tumor growth.

Collectively, the study proposes a coherent model: PRKDC promotes hepatocellular carcinoma progression by upregulating CSF1, activating the CSF1/CSF1R pathway, and inducing M2-like polarization of tumor-associated macrophages, thereby impairing phagocytosis and contributing to immune evasion. This PRKDC-CSF1/CSF1R-tumor-associated macrophage axis may represent a potential therapeutic target in hepatocellular carcinoma, a disease where immune checkpoint inhibitors have shown benefit but where many patients still fail to respond, partly because of the immunosuppressive tumor microenvironment.

The findings carry particular weight because hepatocellular carcinoma is highly lethal and immune evasion is a major barrier to treatment efficacy. Tumor-associated macrophages are abundant in hepatocellular carcinoma and tend to polarize toward an M2-like phenotype, contributing to immune evasion and limiting the impact of immunotherapy. By identifying PRKDC as an upstream regulator of this process, the study adds a new layer to the understanding of how liver tumors manipulate their surroundings and suggests that targeting the PRKDC-CSF1/CSF1R pathway could complement existing immunotherapeutic strategies.

While the research was conducted in mouse models and cell lines, and further work will be needed to confirm the mechanism in human tumors and patients, the study offers a compelling example of how a gene with a well-established role in DNA repair can moonlight as a regulator of immune privilege in cancer. As the field of tumor immunology continues to uncover the complex crosstalk between cancer cells and their microenvironment, studies like this one highlight the importance of looking beyond intrinsic cancer cell pathways to understand how tumors co-opt the immune system for their own survival.

Subject of Research: PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization

Article Title: PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization

Article References: Wang, Y., Pang, W., Lu, X., Wu, H., Li, M., Pan, M., Tan, J., He, J., Luo, Y., Lin, H., Li, M., & Yu, Y. (2026). PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04600-y

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04600-y

Keywords: hepatocellular carcinoma, PRKDC, CSF1, CSF1R, macrophage polarization, tumor microenvironment, immune evasion, phagocytosis, liver cancer, cancer immunology, orchestrates, immune