CXCL1-overexpressing cancer-associated fibroblasts stimulate hepatocellular carcinoma progression via neutrophil recruitment, NET formation, and immune suppression

Sep 23, 2026

Hepatocellular carcinoma is an aggressive malignancy driven by an immunosuppressive tumor microenvironment, where cancer-associated fibroblasts shape immune cell recruitment and function. This study tests how CAF-derived CXCL1 promotes a pro-tumorigenic stroma by manipulating neutrophils. In vitro co-culture and murine models assess HCC progression, using CXCR2 and STAT3 inhibitors and measuring CD8+ T cell activity and NK infiltration. Results show CXCL1 activates neutrophils via CXCR2-STAT3, induces NETs that enhance proliferation and metastasis, and suppresses CD8+ T and NK responses; CXCL1 blockade or pathway inhibition reduces NETs and tumor growth.

LanguageEnglish

CategoryHealthcare

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Pages15

Reading Time38 min

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Abstract

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Cancer Immunology, Immunotherapy (2026) 75:100 [https://doi.org/10.1007/s00262-026-04304-3](https://doi.org/10.1007/s00262-026-04304-3) CXCL1‑overexpressing cancer‑associated fibroblasts stimulate hepatocellular carcinoma progression via neutrophil recruitment, NET formation, and immune suppression Bin Bi1 · Liqin Tang1 · Ranxi Liang1 · Haijing Wu2 · Qilan Huang3 · Li Pan1 Received: 5 June 2025 / Accepted: 11 January 2026 © The Author(s) 2026 Abstract Background Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a prognosis often limited by an immunosuppressive tumor microenvironment (TME) . While cancer-associated fibroblasts (CAFs) are known to influence tumor progression, the specific mechanisms by which they modulate immune cell recruitment and function remain poorly defined. This study investigates how CAF-derived CXCL1 orchestrates a pro-tumorigenic stroma through neutrophil manipulation. Methods The study employed in vitro co-culture systems and in vivo murine models to evaluate the impact of CXCL1-overexpressing CAFs on HCC progression. The signaling mechanisms were assessed using CXCR2 and STAT3 inhibitors, while immune surveillance was monitored via CD8+ T cell activity and natural killer (NK) cell infiltration assays. Result CXCL1 secreted by CAFs was found to activate neutrophils via the CXCR2-STAT3 signaling axis. This activation induces the formation of neutrophil extracellular traps (NETs), which directly facilitate tumor proliferation and metastasis. Furthermore, CXCL1-driven NETs established a potent immunosuppressive TME by significantly impairing CD8+ T cell activity and reducing NK cell infiltration. Conversely, neutralizing CXCL1 or inhibiting the CXCR2-STAT3 pathway successfully suppressed NET formation, restored anti-tumor immune cell functionality, and mitigated tumor growth. Conclusions The CXCL1-CXCR2-STAT3 axis is a critical driver of stromal-immune interactions in HCC. By mediating neutrophil recruitment and NET-driven immune evasion, CAFs create a permissive environment for tumor escalation. Targeting this signaling pathway represents a promising therapeutic strategy to disrupt pro-tumorigenic neutrophil mechanismsand reinvigorate the host’s anti-tumor immunity. Keywords HCC · CAFs · CXCL1 · Neutrophils · CXCR2-STAT3 Bin Bi, Liqin Tang and Ranxi Liang have contributed equally to this work. * Li Pan [panli@scszlyy.org.cn](panli@scszlyy.org.cn) 1 Department of Radiation OncologySichuan Clinical Research Center for CancerSichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Chengdu 610040, Sichuan, China 2 Department of Gynecological Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610040, Sichuan, China 3 Department of Neurology, Chengdu Third Peoples Hospital, Chengdu 610000, Sichuan, China Introduction Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and remains a major clinical challenge due to its high mortality and limited treatment efficacy [6]. Despite advances in diagnosis and therapy, the prognosis for patients with HCC remains poor, largely because of its high metastatic potential and resistance to conventional treatments [7 , 8] . Increasing evidence indicates that the tumor microenvironment (TME) plays a central role in disease progression, with cancer-associated fibroblasts (CAFs) acting as key regulators of tumor-stroma interactions [1, 14, 24 , 50] . CAFs, a heterogeneous population of activated fibroblasts, secrete a repertoire of cytokines and chemokines that stimulate oncogenic processes, including tumor growth, invasion, and immune evasion [20]. Among these, CXCL1, a potent chemokine, has garnered significant attention for its multifaceted role in

FAQs

What role do CXCL1-overexpressing cancer-associated fibroblasts play in hepatocellular carcinoma progression?

They stimulate HCC progression by orchestrating neutrophil recruitment and driving neutrophil extracellular trap (NET) formation, which supports tumor growth and metastasis.

Which signaling pathway mediates CXCL1 effects on neutrophils?

CXCL1 activates neutrophils through the CXCR2-STAT3 signaling axis.

How does blocking CXCL1 or inhibiting CXCR2/STAT3 affect tumor and immune suppression?

Neutralizing CXCL1 or inhibiting CXCR2-STAT3 suppresses NET formation, restores anti-tumor immune cell function, and mitigates tumor growth.

Sep 23, 2026

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