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Tumor Immunotherapy

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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells

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The Double-Edged Sword: How Radiotherapy Shapes the Tumor Immune Microenvironment to Modulate Responses to Checkpoint

Chen-Hsuan Chiang¹, Hui-Wen Chan¹, Hui-Yen Chuang¹

¹Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Yangming Campus, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei 112, Taiwan.

International Journal of Molecular Sciences

|May 27, 2026

Summary

Radiotherapy (RT) is a double-edged sword in cancer treatment, influencing immune checkpoint inhibitors (ICIs). Optimizing RT parameters and targeting tumor metabolism can enhance anti-cancer immunity for precision immuno-oncology.

Keywords:

cGAS-STING ferroptosis immune checkpoint inhibitors immunomodulation radiotherapy tumor metabolism tumor microenvironment

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Area of Science:

Oncology
Immunology
Radiotherapy

Background:

Radiotherapy (RT) traditionally targets cancer via DNA damage.
Emerging evidence shows RT modulates the tumor microenvironment (TME), impacting immune checkpoint inhibitor (ICI) efficacy.
RT's role is a "double-edged sword" in immuno-oncology.

Purpose of the Study:

To analyze the dual immunological effects of RT on the TME.
To assess how RT parameters can be optimized to enhance anti-tumor immunity.
To discuss novel strategies targeting innate immunity and tumor metabolism for improved ICI response.

Main Methods:

Review of current literature on RT and TME interactions.
Analysis of mechanisms underlying RT-induced immune activation and suppression.
Exploration of strategies to overcome RT-induced resistance to ICIs.

Main Results:

RT can act as an in situ vaccine, promoting immunogenic cell death and T-cell infiltration, potentially converting "cold" tumors to "hot" ones.
RT can also promote resistance to ICIs by fostering an immunosuppressive TME.
Optimizing RT dose, fractionation, and particle type (e.g., carbon ion vs. photon) may enhance immune activation.

Conclusions:

RT's impact on the TME presents both opportunities and challenges for ICI therapy.
Strategies modulating innate immunity and tumor metabolism (e.g., ferroptosis) show promise in overcoming immunosuppression.
RT can be strategically integrated into precision immuno-oncology regimens to improve treatment outcomes.