Hidden Enzyme KMT9 Helps Prostate Tumors Evade Immune Attack

Prostate cancer has long been one of the great disappointments of the immunotherapy era. While checkpoint inhibitors have transformed the treatment of melanoma, lung cancer, and a growing list of other malignancies, solid tumors of the prostate have stubbornly refused to respond. The reason, oncologists have come to understand, lies not in the drugs themselves but in the tumor’s surroundings: a densely immunosuppressive tumor immune microenvironment that keeps cytotoxic T cells out of the tumor glands and, when they do arrive, strips them of their killing power. Now, a team of researchers at the University of Freiburg and their collaborators reports that a single epigenetic enzyme sits at the heart of this immune fortress, orchestrating both the physical exclusion of T cells and their functional paralysis.

The enzyme in question is lysine methyltransferase 9, or KMT9, a histone-modifying protein that previous work from the same group had already implicated in prostate tumor growth and androgen receptor signaling. In the new study, published in the journal Molecular Cancer, Jon Peñarando, Eric Metzger, Roland Schüle, and colleagues demonstrate that KMT9 does far more than drive cancer cell proliferation. It actively constructs the molecular barriers that prevent the immune system from recognizing and destroying the tumor, making it a uniquely attractive target for combination approaches designed to sensitize prostate cancer to immunotherapy.

At the center of the discovery is a chemokine signaling axis that functions as a cellular summons for immunosuppressive cells. The researchers found that KMT9 regulates the expression of C-X-C motif chemokine ligands, including CXCL5, which are secreted by prostate tumor cells and bind to the C-X-C motif chemokine receptor 2, CXCR2, on the surface of circulating myeloid cells. This ligand-receptor interaction acts as a homing beacon, drawing polymorphonuclear myeloid-derived suppressor cells, or PMN-MDSCs, into the tumor. Once recruited, these cells populate the tumor immune microenvironment in large numbers, creating a dense myeloid shield around the malignant glands.

PMN-MDSCs are among the most potent enemies of antitumor immunity. They suppress cytotoxic T cell responses through multiple mechanisms, including depletion of the amino acid arginine, production of reactive oxygen species, and interference with T cell trafficking. Using genetically engineered mouse models of prostate cancer in which Pten and Trp53, two frequently altered tumor suppressor genes, are deleted in prostate epithelium, the team showed that tumors with intact KMT9 were heavily infiltrated by these suppressive myeloid cells. When the researchers ablated the Kmt9a gene specifically in the prostate, the picture changed dramatically: PMN-MDSC recruitment collapsed, and cytotoxic T cells flooded into the tumor glands, showing clear signs of activation such as granzyme B expression.

The spatial dimension of this effect proved just as important as the cellular one. Advanced single-cell spatial phenotyping revealed that in tumors with functional KMT9, cytotoxic T cells were largely excluded from the tumor epithelium, lingering instead in the surrounding stroma where they could not make contact with their targets. This immune-excluded pattern is one of the recognized hallmarks of tumors that resist checkpoint blockade, since drugs like anti-PD-1 antibodies can only reinvigorate T cells that are physically close to the cancer cells they are meant to kill. Loss of KMT9 converted this excluded architecture into an inflamed, T cell-infiltrated landscape, precisely the configuration associated with immunotherapy responsiveness.

But KMT9’s contribution to immune evasion did not end with recruitment of suppressor cells. In a second, mechanistically distinct arm of the study, the researchers found that KMT9 also arms the tumor cells themselves against T cell attack. Chromatin immunoprecipitation sequencing showed that KMT9 binds directly to the promoter of the gene encoding arginase 1, ARG1, an enzyme that catabolizes L-arginine, an amino acid essential for T cell function and proliferation. By driving ARG1 expression in prostate tumor cells, KMT9 renders them resistant to T cell-mediated cytotoxicity, effectively allowing them to survive even when killer lymphocytes do manage to engage them.

The therapeutic implications of this dual mechanism were tested in preclinical experiments. When mice carrying Kmt9a-deficient prostate tumors were treated with SB225002, a CXCR2 inhibitor, tumor growth was inhibited to a greater degree than with either intervention alone, confirming that the chemokine axis is a clinically relevant vulnerability downstream of KMT9. Similarly, combining Kmt9a loss with numidargistat, a pharmacological inhibitor of ARG1, produced enhanced suppression of tumor growth. These combination experiments suggest that even partial disruption of the KMT9 pathway could be amplified by drugs that target the individual immune-evasion mechanisms it controls.

Importantly, the team connected their mouse findings to human disease by analyzing data from the TCGA prostate adenocarcinoma cohort, which comprises 500 prostate tumor samples and 52 healthy prostate controls. The analysis showed that KMT9 expression is elevated in prostate tumors relative to normal tissue and that high KMT9 levels correlate with shorter progression-free survival, underscoring the clinical relevance of the pathway. The consistency between the murine genetic models, the human genomic data, and the pharmacological studies lends considerable weight to the conclusion that KMT9 is not an artifact of a single experimental system but a genuine driver of immune evasion in prostate cancer.

For a field searching for ways to unlock immunotherapy in prostate cancer, the study offers a compelling conceptual framework. Rather than targeting the tumor’s defenses one at a time, inhibiting KMT9 would strike at the epigenetic master switch that controls both the recruitment of immunosuppressive myeloid cells through CXCR2 ligand expression and the intrinsic resistance of tumor cells through ARG1. Ablation of KMT9α in the mouse models produced inhibition of prostate tumor growth accompanied by a massive reduction in PMN-MDSC recruitment and a significant increase in cytotoxic T cell activation and infiltration of the tumor glands, a triple effect that few single agents have achieved in this disease.

Considerable work remains before these findings reach the clinic. KMT9 inhibitors are still in early stages of development, and the safety of systemically targeting a methyltransferase with functions in normal tissue is not yet established. The study’s authors note that their findings establish KMT9 as a therapeutic target to reprogram the immunosuppressive landscape and potentially improve the clinical efficacy of current immunotherapies, a formulation that anticipates future trials combining KMT9-directed agents with checkpoint blockade. If those efforts succeed, the stubborn resistance of prostate cancer to immunotherapy, one of the most frustrating puzzles in modern oncology, may finally begin to yield, not to a smarter antibody or a stronger checkpoint inhibitor, but to an epigenetic enzyme that had been quietly building the tumor’s defenses all along.

Subject of Research: The role of the lysine methyltransferase KMT9 in shaping the immunosuppressive tumor immune microenvironment of prostate cancer

Article Title: KMT9 drives T cell exclusion and dysfunction by promoting PMN-MDSCs infiltration and ARG1 expression in prostate cancer

Article References: Peñarando, J., Willmann, D., Sum, M., Jia, Y., Berlin, C., Braun, L. M., Chen, Z., Urban, S., Jung, M., Duteil, D., Metzger, D., Gratzke, C., Zeiser, R., Greschik, H., Schüle, R., & Metzger, E. (2026). KMT9 drives T cell exclusion and dysfunction by promoting PMN-MDSCs infiltration and ARG1 expression in prostate cancer. Molecular Cancer. https://doi.org/10.1186/s12943-026-02801-8

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02801-8

Keywords: KMT9, prostate cancer, tumor immune microenvironment, PMN-MDSCs, CXCL5, CXCR2, ARG1, cytotoxic T cells, cancer immunotherapy, epigenetics, histone methyltransferase, immune evasion