IL-15 signaling via cis-and trans-presentation to progenitor-exhausted CD8+ T cells enhances radio-immunotherapy efficacy in ESCC

Sep 29, 2026

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Research on locally advanced esophageal squamous cell carcinoma (ESCC) shows variability in patient response to concurrent chemoradiotherapy with PD-1/PD-L1 targeting immunotherapy, making predictive biomarkers necessary. This study evaluates IL-15’s role using clinical cohorts with blood and tissue samples collected before and during radiotherapy. A multi-omics workflow integrating ELISA, flow cytometry, single-cell RNA sequencing, and spatial analysis links elevated IL-15 to improved prognosis. IL-15 mainly originates from macrophages, endothelial cells, dendritic cells, and CD4+ T cells, supporting IL-15 pathway activation and stemness maintenance in progenitor-exhausted CD8+ T cells. Results indicate IL-15 as a potential biomarker and therapeutic target.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Background

ESCC treatment and need for biomarkers

IL-15 biology and receptor signaling

Methods

Clinical cohorts and sample collection

Multi-omics profiling

Results

Prognostic association of IL-15 during RT plus immunotherapy

IL-15 cellular sources and cis/trans presentation

Role of spatial proximity in the tumor microenvironment

Preclinical efficacy in mouse models

Conclusions

You et al. Journal of Nanobiotechnology (2026) 24:13 [https://doi.org/10.1186/s12951-025-03881-2](https://doi.org/10.1186/s12951-025-03881-2) Journal of Nanobiotechnology RESEARCH Open Access IL-15 signaling via cis-and trans-presentation to progenitor-exhausted CD8+ T cells enhances radio-immunotherapy efficacy in ESCC Yi You 1†, Linrui Gao 1†, Shijia Li 1†, Hui Huang 1, Tierun Wang 1, Zongchang Nie 1, Jian Zhou2, Xiaoxue Ma 1, Jiarui Li2, Hongyu Bie2, Tian Zhang 1, Xi Chen 1, Qingsong Pang 1, Ping Wang 1, Cihui Yan2,4* and Wencheng Zhang 1,3* Abstract Background Concurrent chemoradiotherapy (CRT) combined with PD-1/PD-L1 targeting immunotherapy (IM) has emerged as a promising treatment for locally advanced esophageal squamous cell carcinoma (ESCC) . However, individual responses to this treatment vary, highlighting the need for predictive biomarkers to improve therapeutic efficacy. Interleukin-15 (IL-15) has shown potential in enhancing anti-tumor immunity, but its role in ESCC remains poorly defined. Methods We analyzed clinical cohorts of ESCC patients who underwent radiotherapy (RT) and IM, utilizing blood and tissue samples collected pre-and during treatment. A multi-omics approach combining ELISA, flow cytometry, single-cell RNA sequencing, and spatial analysis was employed to investigate the role of IL-15 within the tumor microenvironment (TME) . Results Elevated IL-15 levels during RT combined with IM correlated with improved patient prognosis. IL-15 was predominantly expressed by macrophages, endothelial cells, dendritic cells, and CD4+ T cells. It enhanced the activation and maintenance of stemness in progenitor-exhausted CD8+ T (Tpex) cells via trans-or cis-presentation. The spatial proximity between presenting cells andTpex cells was crucial for activating the IL-15 pathway and promoting immune responses within the TME. Additionally, preclinical mouse models demonstrated that combining RT, anti-PD-1, and IL-15/IL-15 receptor alpha treatment resulted in significant anti-tumor effects. Conclusions Our findings suggest that IL-15 levels could serve as a biomarker for identifying ESCC patients who are likely to benefit from RT and IM. These results also provide a rationale for targeting IL-15 as a novel therapeutic strategy to enhance treatment outcomes for ESCC patients. †Yi You, Linrui Gao and Shijia Li contributed equally to this work. *Correspondence: Cihui Yan [cihuiyan@tmu.edu.cn](cihuiyan@tmu.edu.cn)[ ](cihuiyan@tmu.edu.cn)Wencheng Zhang [wczhang@tmu.edu.cn](wczhang@tmu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. You et al. Journal of Nanobiotechnology (2026) 24:13 Page 2 of 19 Keywords IL-15, CD8+ T cell, Esophageal squamous cell carcinoma, Radiotherapy, Immunotherapy Graphical abstract Background Esophageal cancer (EC) is the 11th most commonly diagnosed cancer and the seventh

FAQs

为什么需要针对 ESCC 的治疗疗效预测生物标志物？

联合放化疗及 PD-1/PD-L1 靶向免疫治疗虽然有前景，但不同患者的反应存在明显差异，因此需要可靠的预测生物标志物以提升疗效评估与治疗选择。

研究如何评估 IL-15 在治疗中的作用？

通过对接受放疗并联合免疫治疗的 ESCC 临床队列进行分析，使用放疗前与放疗过程中的血液和组织样本，并结合 ELISA、流式细胞术、单细胞 RNA 测序与空间分析等多组学方法。

IL-15 与前体衰竭型 CD8+ T 细胞之间的关键机制是什么？

IL-15 通过跨呈递或顺呈递增强前体衰竭型 CD8+ T（Tpex）细胞的激活与干性维持；同时，呈递细胞与 Tpex 细胞之间的空间邻近性对 IL-15 通路激活与肿瘤微环境内免疫反应至关重要。

Sep 29, 2026

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