Disruption of ACTG1 potentiates anti-TIM-3 immunotherapy by reprogramming the immunosuppressive microenvironment via the CSF3/CSF3R axis in pancreatic cancer
6 affiliations
- 1Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University
- 2Department of General Surgery, Huashan Hospital and Cancer Metastasis Institute, Fudan University
- 3Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University
- 4College of Acupuncture-moxibustion, Anhui University of Chinese Medicine
- 5Traditional Chinese Medicine Department, Minhang Hospital, Fudan University
- 6Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy
Abstract
Background: The limited immune infiltration observed in pancreatic ductal adenocarcinoma (PDAC) is a major factor contributing to immunotherapy resistance and the consistently poor prognosis. Hence, identifying novel therapeutic targets and developing effective combination strategies to overcome immunotherapy resistance represent urgent and unmet clinical needs.
Methods: The gene expression datasets and corresponding clinical information were collected from TCGA, GEO and ICGC. The immune cell infiltration (ICI) contents were evaluated by “CIBERSORT”. PDAC subtypes based on ICI pattern were obtained from consensus clustering. Their prognostic value was validated by the Kaplan-Meier survival curves. Then, we employed an integrated multi-dataset approach to systematically identify pivotal regulators of PDAC progression. The functional role of ACTG1 was specifically validated through in vivo and in vitro models. The tumor immune microenvironment was characterized by flow cytometry and immunohistochemistry (IHC). Potential molecular mechanisms were further investigated using RNA sequencing and tumor cell-macrophage co-culture experiments.
Results: Three distinct immune infiltration subtypes with different prognoses and immunological features were identified in the 608-sample GEO/ICGC training cohort and the 177-sample TCGA-PAAD validation cohort. The ICI pattern with a better prognosis was characterized by high level of plasma cells, activated NK cells, activated DC cells, M1 macrophages and CD8 ⁺ T cells, low level of M0 macrophages, M2 macrophages. ACTG1 drives immunosuppression and predicts poor prognosis in PDAC. Mechanistically, ACTG1 promotes tumor cell-derived CSF3 secretion, which upregulates TIM-3 expression on tumor-associated macrophages (TAMs) via the CSF3/CSF3R signaling pathway. This cascade reinforces M2-like TAMs polarization and induces CD8 ⁺ T cell exhaustion, thereby fostering an immunosuppressive niche. Strikingly, ACTG1 knockdown combined with TIM-3 blockade exerts an enhanced effect in reversing immunosuppression, restoring anti-tumor immunity, and markedly prolonging survival.
Conclusions: ACTG1 promotes PDAC progression by orchestrating an immunosuppressive tumor microenvironment through the CSF3/CSF3R/TIM-3 axis. Thus, combining genetic suppression of ACTG1 with TIM-3 blockade represents a potent therapeutic approach to overcome immune evasion and curb tumor progression.
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BibTeX
@article{zhu2026disruption,
title = {{Disruption of ACTG1 potentiates anti-TIM-3 immunotherapy by reprogramming the immunosuppressive microenvironment via the CSF3/CSF3R axis in pancreatic cancer}},
author = {Le Zhu and Yu Guo and Xinxin Ling and Yuqi Tao and Shun Wang and Sanfeng Han and Meiping Ni and Huarong Mao and Jiajun Wu and Chengjie Zhang and Ziping Zhang and Qimeng Chang and Zhiqiu Hu and Junmin Chen and Bingsheng Sun and Xiaodi Yang and Qiongzhu Dong},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1820470},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1820470/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Disruption of ACTG1 potentiates anti-TIM-3 immunotherapy by reprogramming the immunosuppressive microenvironment via the CSF3/CSF3R axis in pancreatic cancer
AU - Le Zhu
AU - Yu Guo
AU - Xinxin Ling
AU - Yuqi Tao
AU - Shun Wang
AU - Sanfeng Han
AU - Meiping Ni
AU - Huarong Mao
AU - Jiajun Wu
AU - Chengjie Zhang
AU - Ziping Zhang
AU - Qimeng Chang
AU - Zhiqiu Hu
AU - Junmin Chen
AU - Bingsheng Sun
AU - Xiaodi Yang
AU - Qiongzhu Dong
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1820470
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1820470/full
AB - Background: The limited immune infiltration observed in pancreatic ductal adenocarcinoma (PDAC) is a major factor contributing to immunotherapy resistance and the consistently poor prognosis. Hence, identifying novel therapeutic targets and developing effective combination strategies to overcome immunotherapy resistance represent urgent and unmet clinical needs. Methods: The gene expression datasets and corresponding clinical information were collected from TCGA, GEO and ICGC. The immune cell infiltration (ICI) contents were evaluated by “CIBERSORT”. PDAC subtypes based on ICI pattern were obtained from consensus clustering. Their prognostic value was validated by the Kaplan-Meier survival curves. Then, we employed an integrated multi-dataset approach to systematically identify pivotal regulators of PDAC progression. The functional role of ACTG1 was specifically validated through in vivo and in vitro models. The tumor immune microenvironment was characterized by flow cytometry and immunohistochemistry (IHC). Potential molecular mechanisms were further investigated using RNA sequencing and tumor cell-macrophage co-culture experiments. Results: Three distinct immune infiltration subtypes with different prognoses and immunological features were identified in the 608-sample GEO/ICGC training cohort and the 177-sample TCGA-PAAD validation cohort. The ICI pattern with a better prognosis was characterized by high level of plasma cells, activated NK cells, activated DC cells, M1 macrophages and CD8 ⁺ T cells, low level of M0 macrophages, M2 macrophages. ACTG1 drives immunosuppression and predicts poor prognosis in PDAC. Mechanistically, ACTG1 promotes tumor cell-derived CSF3 secretion, which upregulates TIM-3 expression on tumor-associated macrophages (TAMs) via the CSF3/CSF3R signaling pathway. This cascade reinforces M2-like TAMs polarization and induces CD8 ⁺ T cell exhaustion, thereby fostering an immunosuppressive niche. Strikingly, ACTG1 knockdown combined with TIM-3 blockade exerts an enhanced effect in reversing immunosuppression, restoring anti-tumor immunity, and markedly prolonging survival. Conclusions: ACTG1 promotes PDAC progression by orchestrating an immunosuppressive tumor microenvironment through the CSF3/CSF3R/TIM-3 axis. Thus, combining genetic suppression of ACTG1 with TIM-3 blockade represents a potent therapeutic approach to overcome immune evasion and curb tumor progression.
SN - 1664-3224
ER -