Immunomodulation Techniques in Cancer Radiotherapy

Radiotherapy is increasingly appreciated not only for its direct cytotoxic effects but also for its capacity to reshape the immune landscape of tumours. Ionising radiation induces DNA damage that can trigger immunogenic cell death, characterised by release of danger signals and tumour antigens. Concomitantly, radiation modulates the tumour microenvironment by upregulating antigen presentation pathways, chemokine secretion and expression of immune checkpoints such as PD-L1. Modern approaches exploit these properties to amplify antitumour immunity: combinations of radiotherapy with immune checkpoint inhibitors reinvigorate exhausted T cells; targeted enzymatic agents enhance exposure of “eat-me” signals like calreticulin; and advanced modalities such as proton and carbon ion beams offer superior dose conformity and unique biological effects that further invigorate immune activation. Moreover, strategic partial‐volume or hypoxia‐guided irradiation can harness bystander and abscopal phenomena, provoking systemic responses beyond the irradiated field. Emerging research also explores the induction of regulated cell-death programs—such as ferroptosis—to yield distinct immunostimulatory profiles. Collectively, these techniques herald a paradigm shift in which radiotherapy functions as both a local tumour-debulking tool and a systemic immunomodulatory platform, with the potential to improve clinical outcomes across diverse cancer types.

Research from Nature Portfolio

Recent studies have revealed how DNA damage responses regulate immune checkpoint expression in irradiated tumour cells. Mechanistic work shows that activation of the ATM–ATR–Chk1 axis following double-strand breaks leads to upregulation of PD-L1, linking repair pathways with immune evasion. Depletion of key repair factors such as BRCA2 or the Ku70/80 complex potentiates this response, illustrating the interplay between genotoxic stress and checkpoint signalling. In parallel, investigations into PD-L1 dynamics in bladder carcinoma demonstrate that radiotherapy-induced PD-L1 expression correlates with disease stage and treatment outcomes, while blockade of PD-L1 enhances radiosensitivity and antitumour T-cell activity. Together, these foundational studies establish the mechanistic basis for combining radiotherapy with immune checkpoint modulation and inform the design of next-generation radiotherapy–immunotherapy regimens.

Immunomodulation Techniques in Cancer Radiotherapy publication trend

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

Technical terms

Immunogenic cell death (ICD): A form of cell death that stimulates adaptive immune responses by releasing danger signals and tumour antigens.

Immune checkpoint inhibitor (ICI): Antibody or molecule that blocks inhibitory receptors on immune cells to enhance antitumour immunity.

Programmed death-ligand 1 (PD-L1): A checkpoint protein on tumour and immune cells that binds PD-1 on T cells to dampen immune responses.

Tumour microenvironment (TME): The complex milieu of immune cells, stromal elements and signalling molecules surrounding a tumour.

Abscopal effect: Systemic antitumour response at sites distant from the irradiated field.

Ferroptosis: Iron-dependent regulated cell death marked by lipid peroxidation and associated with immune activation.

Calreticulin (CRT): Endoplasmic reticulum protein that relocalises to the cell surface as an “eat-me” signal during ICD.

Myeloid-derived suppressor cells (MDSCs): Immunosuppressive myeloid-lineage cells that inhibit T-cell activity within tumours.

References

1. The combination of calreticulin-targeting L-ASNase and anti-PD-L1 antibody modulates the tumor immune microenvironment to synergistically enhance the antitumor efficacy of radiotherapy. Theranostics (2024).
2. Effect of Proton Therapy on Tumor Cell Killing and Immune Microenvironment for Hepatocellular Carcinoma. Cells (2023).
3. Carbon ion radiotherapy combined with immunotherapy: synergistic anti-tumor efficacy and preliminary investigation of ferroptosis. Cancer Immunology, Immunotherapy (2023).
4. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nature Communications (2017).
5. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Scientific Reports (2016).
6. Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects. Radiation Oncology (2019).
7. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget (2013).