Radiotherapy Backfires: PD-1-Positive Monocytes Emerge as Hidden Drivers of Treatment Resistance

Radiotherapy has long been one of the most dependable weapons in the oncologist’s arsenal, delivering precisely targeted doses of ionizing radiation to destroy malignant cells while sparing healthy tissue. Yet for all its power, a stubborn clinical reality persists: many solid tumors either fail to respond fully to radiation or acquire resistance over the course of treatment, and the underlying biology of that failure has remained frustratingly opaque. A new study published in Cancer Immunology, Immunotherapy by Jiandong Zhang, Chen Chen, Qiuyu Mu, Yuzhu Hou, Xiaozhi Zhang and colleagues offers a striking explanation, and it centers on an unexpected cast of characters within the tumor microenvironment: monocytes that suddenly begin displaying a molecule most famous for its role in shutting down T cells.

The molecule in question is PD-1, or programmed cell death protein 1, a receptor best known as the target of the blockbuster class of cancer immunotherapies called immune checkpoint inhibitors. PD-1 normally acts as a molecular brake on immune responses, and tumors exploit this brake by co-opting the PD-1/PD-L1 axis to paralyze cytotoxic T lymphocytes, the immune system’s primary tumor-killing cells. What makes the new findings so provocative is that the researchers found radiotherapy itself, a treatment intended to unleash anti-tumor immunity, drives PD-1 expression onto tumor-associated monocytes, converting these cells into immunosuppressive agents that undermine the very immune attack radiation is supposed to provoke.

Monocytes are circulating white blood cells that can be recruited into tissues, including tumors, where they differentiate into macrophages and related myeloid cells. Within the tumor microenvironment, these myeloid cells often take on a suppressive phenotype, dampening T cell activity and fostering an immunologically cold milieu that resists both immunotherapy and other treatments. The new study demonstrates that after radiotherapy, a distinct subset of tumor-associated monocytes upregulates PD-1, and that these PD-1-positive monocytes actively suppress the anti-tumor activity of CD8-positive T cells, the cytotoxic lymphocytes responsible for recognizing and destroying cancer cells.

Perhaps the most technically significant contribution of the work is the delineation of the signaling pathway that connects radiation to PD-1 induction on monocytes. According to the researchers, radiotherapy triggers the adenosine-A2AR-cAMP-PKA-NF-κB axis. In this cascade, adenosine, a purine nucleoside that accumulates in stressed and damaged tissues, engages the A2A adenosine receptor (A2AR) on the monocyte surface. Receptor activation raises intracellular cyclic AMP (cAMP), which in turn activates protein kinase A (PKA), ultimately engaging the transcription factor NF-κB to drive PD-1 expression. This pathway is a classic example of how tissue damage signals can be hijacked by tumors: adenosine is abundant in the hypoxic, metabolically stressed environment of irradiated tumors, and the study shows that this damage-associated molecule becomes the trigger for an immunosuppressive monocyte program.

The functional consequences of this conversion are substantial. When PD-1-positive monocytes accumulate after radiation, they suppress the activity of CD8-positive T cells, blunting the immune-mediated tumor killing that radiation therapy is known to promote through mechanisms such as immunogenic cell death and antigen release. In other words, radiation delivers a double-edged signal: it damages tumor cells in ways that should alert the immune system, but it simultaneously generates a myeloid cell population that mutes that alert. This may help explain a long-standing puzzle in radiation oncology, namely why the much-discussed abscopal effect, in which localized radiation provokes systemic tumor regression, occurs so rarely in clinical practice.

Critically, the researchers did not stop at mechanistic description. They showed that targeting this PD-1-positive monocyte subset enhanced the efficacy of radiotherapy in their experimental models, suggesting that depleting or inhibiting these cells could convert a partially resistant tumor into one that responds robustly to radiation. This therapeutic implication is significant because it points toward combination strategies: rather than simply escalating radiation doses, which risks toxicity, clinicians could in principle pair standard radiotherapy with agents that prevent monocyte PD-1 induction or eliminate the suppressive subset altogether.

The clinical relevance of the findings received direct support from human tissue analysis. The team examined tissues from patients whose tumors had proven resistant to radiotherapy and found elevated infiltration of PD-1-positive monocytes compared with what would be expected in a responsive setting. This correlation between the presence of the suppressive monocyte subset and treatment failure in patients elevates the work beyond a laboratory observation and suggests that the pathway identified in preclinical models operates in human disease. If validated in larger cohorts, PD-1-positive monocyte infiltration could serve as a biomarker predicting which patients are likely to resist radiotherapy and therefore need combination treatment from the outset.

The study also reframes the ongoing conversation about PD-1 as a therapeutic target. Checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies were developed to release the brake on T cells, and they have transformed outcomes in melanoma, lung cancer and many other malignancies. But the new findings indicate that PD-1 biology extends beyond T cells: myeloid cells expressing PD-1 after radiation represent a separate, radiation-induced reservoir of immunosuppression. This raises intriguing questions about whether PD-1-targeting drugs exert some of their effects through monocytes rather than exclusively through T cells, and whether patients receiving radiotherapy might benefit from checkpoint blockade precisely because it neutralizes the radiation-induced monocyte program.

From a broader perspective, the work exemplifies a growing appreciation that the success or failure of cancer treatment is decided not only by the intrinsic sensitivity of tumor cells but by the ecosystem surrounding them. The tumor microenvironment is a dense network of immune, stromal and vascular components that respond dynamically to therapy. Radiation-induced cell death releases damage-associated molecular patterns, including adenosine, and the new study shows how one such signal is translated, through a defined receptor-second messenger-transcription factor cascade, into a durable immunosuppressive state. Understanding these feedback loops at the molecular level is essential if combination therapies are to be designed rationally rather than empirically.

For patients and clinicians, the immediate takeaway is one of cautious optimism. The identification of the adenosine-A2AR-cAMP-PKA-NF-κB pathway and the suppressive PD-1-positive monocyte subset it generates offers multiple potential points of intervention, from adenosine receptor antagonists to strategies that deplete the monocyte subset, and the demonstration that targeting these cells boosts radiotherapy efficacy provides a proof of principle. Translating that principle into the clinic will require further validation, safety assessment and well-designed trials, but the study supplies a clear mechanistic target for overcoming one of radiotherapy’s most persistent limitations. As the authors conclude, depleting this distinct immunosuppressive monocyte subset that accumulates after radiation represents a promising strategy to overcome resistance and strengthen anti-tumor immunity, a conclusion that could reshape how radiation oncology and immunotherapy are combined in the years ahead.

Subject of Research: Radiotherapy-induced PD-1 expression on tumor-associated monocytes and its role in immunosuppression and radioresistance

Article Title: Radiotherapy drives PD-1 expression on monocytes to attenuate anti-tumor immunity

Article References: Zhang, J., Chen, C., Mu, Q., Hou, Y., & Zhang, X. (2026). Radiotherapy drives PD-1 expression on monocytes to attenuate anti-tumor immunity. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04519-4

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04519-4

Keywords: radiotherapy, PD-1, monocytes, tumor microenvironment, radioresistance, CD8-positive T cells, adenosine, A2A receptor, NF-kB, immunotherapy, cancer resistance, myeloid cells