Single-fraction radiotherapy with a bioactive depot of CD39 blockade eradicates malignant tumors

  • J Control Release. 2026 Mar 10:391:114632. doi: 10.1016/j.jconrel.2026.114632.
Chunlian Ye  1 ,  Yun Zheng  2 ,  Huilan He  2 ,  Jinlong Ji  1 ,  Liang Liu  1 ,  Yu Sun  1 ,  Yuwei Peng  2 ,  Shenqiang Wang  3 ,  Ying Zhang  4 ,  Zhiyuan Zhong  5
Affiliations
  • 1. College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
  • 2. College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 3. College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 4. College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
  • 5. College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
PMID: 41539607 DOI: 10.1016/j.jconrel.2026.114632
Abstract

The efficacy of radio-immunotherapy is generally limited by adaptive resistance mechanisms that create an immunosuppressive tumor microenvironment. The molecular drivers of this radio-resistance remain poorly defined. Here we identify the ectonucleotidase CD39 as a critical driver of radiotherapy (RT)-induced immunosuppression. We show that RT robustly upregulates CD39 on tumor cells and tumor-infiltrating immune cells, creating an adenosine-rich tumor microenvironment that promotes immune evasion. Pharmacological inhibition of CD39 with POM-1 reverses this immunosuppression, synergizing with RT to enhance anti-tumor immunity. Furthermore, we engineer an immuno-gel (POM-1@iGel) for sustained local CD39 inhibition and concurrent immune stimulation. A single intratumoral injection of POM-1@iGel in combination with single-fraction RT establishes durable systemic anti-tumor immunity with immunological memory and leads to complete tumor regression in a murine colorectal Cancer model. These findings elucidate a critical mechanism of RT-induced immune escape and present a rational, scalable strategy to overcome RT-induced immunosuppression and boost radio-immunotherapy in solid tumors.

Keywords
CD39 blockade; Cancer immunotherapy; Immunosuppressive marker; Injectable hydrogels; Systemic anti-tumor immunity.
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