Immunomodulation Strategies in Radiation Oncology

Radiation therapy has long been a cornerstone of cancer treatment, exerting its primary effect through direct DNA damage and tumour cell death. In recent years, however, there has been growing recognition that ionising radiation also profoundly reshapes the immune landscape within and beyond irradiated sites. By altering antigen presentation, inflammatory signalling and immune-cell recruitment, radiotherapy can convert the tumour into an in situ vaccine and potentiate systemic antitumour immunity. Conversely, radiation can induce immunosuppressive pathways and substitute myeloid-derived suppressor cells or regulatory T cells, thereby fostering radioresistance. Contemporary strategies in radiation oncology therefore focus on tipping the balance towards immunostimulation. Approaches include optimising dose and fractionation to maximise the release of danger signals, combining radiation with agonists of innate pathways such as cGAS–STING, exploiting radiation-induced neoantigens to enhance checkpoint blockade, and deploying local or low-dose radiation to inflame otherwise immune-cold tumours. The ultimate objective is to orchestrate synergistic interactions between radiotherapy and immunomodulatory agents, yielding durable tumour control and abscopal responses across diverse cancer types.

Research from Nature Portfolio

Recent studies have defined how distinct immune compartments can be co-targeted to overcome resistance in poorly immunogenic tumours. One investigation demonstrated that combining radiation with cytotoxic T-lymphocyte antigen-4 blockade expands CD4+ helper cells and enriches exhausted CD8+ clones, yet durable responses require engagement of antigen-presenting cells via a CD40 agonist. This tri-modality regimen remodels the tumour microenvironment, reduces regulatory T cells and promotes effector-memory CD8+ subsets linked to improved survival. In another foundational work, the DNA exonuclease Trex1 was identified as a key regulator of radiation-driven immunogenicity. Doses above a critical threshold induce Trex1 expression, which degrades cytosolic DNA and attenuates type I interferon production via the cGAS–STING axis. Fractionated protocols that avoid Trex1 induction sustain interferon-β release, recruit Batf3-dependent dendritic cells and prime CD8+ T cells for systemic tumour rejection. These findings underscore the importance of tailoring dose and timing to harness innate sensing pathways and optimise synergy with immune checkpoint therapy.

Immunomodulation Strategies in Radiation Oncology publication trend

The graph below shows the total number of articles in immunomodulation strategies in radiation oncology across all publications each year (not limited to Nature Index journals).

Technical terms

Tumour microenvironment (TME): The complex network of cancer cells, immune cells, blood vessels and stromal elements surrounding a tumour.

cGAS–STING pathway: An innate immune sensing cascade activated by cytosolic DNA that triggers type I interferon production.

Abscopal effect: Systemic antitumour responses at sites distant from the irradiated region, mediated by immune mechanisms.

Immune checkpoints: Regulatory receptors such as CTLA-4 and PD-1 on T cells that modulate immune activation and tolerance.

Myeloid-derived suppressor cells (MDSCs): A heterogeneous population of immature myeloid cells that inhibit T-cell function and foster tumour progression.

Immunogenic cell death: A form of cell demise that releases danger signals and neoantigens to stimulate adaptive immunity.

References

1. Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors. Nature Communications (2023).
2. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nature Communications (2017).
3. Radiation effects on antitumor immune responses: current perspectives and challenges. Therapeutic Advances in Medical Oncology (2018).
4. Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to ImmunotherapyLow-Dose Radiation Enables Tumor Immune Responsiveness. Cancer Discovery (2021).
5. A self‐assembled, genetically engineered, irradiated tumor cell debris vaccine. Exploration (2024).