PARP inhibitor radiosensitization enhances anti-PD-L1 immunotherapy through stabilizing chemokine mRNA in small cell lung cancer

Sep 23, 2026

Uploaded by Ezra

Immunotherapy yields limited benefits in small cell lung cancer (SCLC) partly because tumors produce insufficient chemokines, leading to poor cytotoxic T-cell infiltration. The study tests PARP inhibitors (olaparib, talazoparib, veliparib) combined with radiotherapy in SCLC models, showing enhanced immune activation and anti-tumor efficacy. Mechanistically, the regimen activates cGAS-STING, elevates CCL5 and CXCL10 mRNAs, and stabilizes CXCL10 mRNA via an EIF4E2-dependent process. Adding anti-PD-L1 further increases T-cell infiltration and function, supporting PARPi-RT-anti-PD-L1 as a strategy for SCLC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Background

Immunotherapy limitations in SCLC

Need to improve T-cell infiltration

Study approach

PARP inhibitors with radiotherapy

Combination with continued PARPi delivery

Mechanistic findings

cGAS-STING activation and chemokine induction

EIF4E2-dependent CXCL10 mRNA stabilization

Therapeutic combination outcome

Adding anti-PD-L1 to PARPi-RT

Article [https://doi.org/10.1038/s41467-025-57257-z](https://doi.org/10.1038/s41467-025-57257-z) PARP inhibitor radiosensitization enhances anti-PD-L1 immunotherapy through stabilizing chemokine mRNA in small cell lung cancer Received: 16 May 2023 | Accepted: 17 February 2025 | | --- | | | | Check for updates | Xiaozhuo Ran1, Bell Xi Wu1,2, Venkatasubramanian Vidhyasagar1, Lifang Song1, Xu Zhang3,4, Reese Jalal Ladak3,4, Mona Teng1,2, Wail Ba-alawi1, Vivek Philip1, Housheng H. He 1,2, Nahum Sonenberg 3,4 & Benjamin H. Lok 1,2,5,6 Immunotherapy (IO) is an effective treatment for various cancers; however, the beneﬁts are modest for small cell lung cancer (SCLC). The poor response of SCLC to anti-PD-1/PD-L1 IO is due in part to the lack of cytotoxic T cells because of limited chemokine expression from SCLC tumors. Immunogenic radiosensitizers that enhance chemokine expression may be a promising strategy forward. Here, we show that the PARP inhibitors (PARPi), including olaparib, talazoparib and veliparib, in combination with radiotherapy (RT) enhance the immune activation and anti-tumor efﬁcacy in SCLC cell lines, patient-derived xenograft (PDX) and syngeneic mouse models. The effect is further enhanced by continued delivery of adjuvant PARPi. The combination treatment (PARPi with RT) activates the cGAS-STING pathway and increases the mRNA levels of the T cell chemo-attractants CCL5 and CXCL10. In addition to upregulation of transcription, the combination treatment increases chemokine CXCL10 protein levels via stabilization of CXCL10 mRNA in an EIF4E2-dependent manner. The incorporation of anti-PD-L1IO into the PARPi with RT combination therapy further improves the anti-tumor efﬁcacy by increasing T cell inﬁltration and function. This study thus provides a proof of principle for the combination of PARP inhibitors, RT and anti-PD-L1 IO as a treatment strategy for SCLC. Small cell lung cancer (SCLC) is a highly aggressive lung cancer subtype with poor prognosis1. Despite the use of chemotherapy and selective use of radiotherapy (RT) as standard treatments, the ﬁve-year survival rate for patients with extensive-stage SCLC (ES-SCLC) is less than 5%. Immunotherapy (IO) is effective against various cancers, including melanoma, non-small cell lung cancer, MSI-high colorectal cancer, head and neck cancer, and among other malignancies2–6. Most IO therapeutics block checkpoint proteins or their partners to prevent inhibitory signals for T cells, allowing T cells to access and perform their cytotoxic anti-tumor function7. In 2018, for patients with ESSCLC, a landmark clinical trial of atezolizumab (anti-PD-L1) in combination with chemotherapy demonstrated the ﬁrst improvement in overall survival (OS) in a phase III study of systemic agents in over 30 years8. However, the OS beneﬁt was relatively small, with a median OS 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 2Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. 3Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada. 4Department of Biochemistry, McGill University, Montreal, QC, Canada. 5Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. 6Department of Radiation Oncology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. e-mail: [benjamin.lok@uhn.ca](benjamin.lok@uhn.ca) of 12.3 months with atezolizumab compared to 10.3 months with chemotherapy alone. Additionally, the median progression-free survival (PFS) gain was less than one month. Similar results were also observed in another trial of durvalumab (anti-PD-L1) in combination with platinum-etoposide, in which the median OS was 2 months longer than the platinum-etoposide group9. These results suggest that while the combination of IO with chemotherapy may be beneﬁcial for some patients with SCLC, the overall survival beneﬁt

FAQs

Why does small cell lung cancer respond poorly to anti-PD-1/PD-L1 immunotherapy?

The response is limited partly by reduced cytotoxic T cells, driven in part by insufficient chemokine expression from SCLC tumors.

What combination strategy did the study evaluate for SCLC?

The study evaluated PARP inhibitors together with radiotherapy, including continued delivery of adjuvant PARP inhibitors, and then incorporated anti-PD-L1 into the combination.

How does the PARP inhibitor plus radiotherapy regimen increase chemokine levels?

It activates the cGAS-STING pathway, raises CCL5 and CXCL10 mRNA levels, and increases CXCL10 protein by stabilizing CXCL10 mRNA in an EIF4E2-dependent manner.

Sep 23, 2026

Uploaded by Ezra