Journal Article

Enhancing anti-tumor immunity by targeting BATF and the STAT1/PD-L1 pathway in cervical carcinoma

Zhu, Yuanyuan, Peng, Xing, Cai, Chunyan, Han, Yaqing

2025

Overview

Background Cervical carcinoma remains a leading cause of cancer-related mortality in women worldwide, with poor prognosis often linked to immune evasion mechanisms. The Basic Leucine Zipper Activating Transcription Factor (BATF) has emerged as a critical regulator of T-cell functionality, yet its role in cervical cancer progression and immune modulation remains poorly understood. This study investigates the role of BATF in cervical carcinoma, focusing on its effects on tumor progression, immune modulation, and immune checkpoint regulation, to identify BATF as a therapeutic target to enhance anti-tumor immunity. Methods BATF expression was analyzed in cervical cancer tissues and cell lines. Functional assays, including cell proliferation, migration, and invasion, were performed following BATF knockdown. In vivo studies assessed tumor growth and metastasis in xenograft models. Immune cell populations, cytokine production, and immune checkpoint expression were analyzed using flow cytometry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and immunohistochemistry. Mechanistic studies evaluated BATF regulation of programmed cell death-ligand 1 (PD-L1) through the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Finally, the therapeutic potential of BATF knockdown in combination with PD-L1 blockade was evaluated in vivo. Results Analysis of patient-derived samples and cell lines revealed that BATF is overexpressed in cervical cancer and correlates with poor prognosis. Functional studies demonstrated that BATF promotes tumor proliferation, epithelial-to-mesenchymal transition (EMT), migration, and invasion. In vivo, BATF knockdown significantly suppressed tumor growth and metastasis in xenograft models. Immune profiling revealed that BATF deficiency enhanced antitumor immunity by increasing CD8⁺ and CD4⁺ T-cell infiltration, increasing the production of CD8⁺ cytotoxic molecules such as granzyme B and IFN-γ while reducing tumor-associated macrophages and immune checkpoint expression, including Programmed death 1 (PD-1), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and Lymphocyte activation gene-3 (LAG-3.) Mechanistically, BATF regulated PD-L1 expression via the STAT1 signaling pathway, promoting immune evasion. Combination therapy with BATF knockdown and anti-PD-L1 antibodies significantly enhanced anti-tumor immunity and inhibited tumor growth compared to monotherapy. Conclusions BATF plays a pivotal role in cervical cancer progression and immune evasion by regulating the STAT1/PD-L1 axis and modulating the tumor immune microenvironment. Targeting BATF, alone or in combination with immune checkpoint inhibitors (PD-L1), represents a promising therapeutic strategy to improve outcomes in cervical cancer patients. Further research is warranted to translate these findings into clinical applications.

• Publisher: Springer International Publishing,Springer Nature B.V,Springer
• Subject: Animals / Apoptosis / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Basic-Leucine Zipper Transcription Factors - antagonists & inhibitors / Basic-Leucine Zipper Transcription Factors - genetics / Basic-Leucine Zipper Transcription Factors - metabolism / BATF / Biochemistry / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer therapies / CD223 antigen / CD4 antigen / CD8 antigen / Cell activation / Cell Biology / Cell culture / Cell death / Cell Line, Tumor / Cell Movement / Cell Proliferation / Cervical cancer / Cervical carcinoma / Cervix / Cytotoxicity / Female / Flow cytometry / Gene Expression Regulation, Neoplastic / Human papillomavirus / Humans / Immune checkpoint inhibitors / Immune response / Immune system / Immunity / Immunity (Disease) / Immunohistochemistry / Immunomodulation / Immunotherapy / In vivo methods and tests / Leucine / Leukocyte migration / Life Sciences / Lymphocytes / Lymphocytes T / Macrophages / Metastases / Mice / Mice, Inbred BALB C / Mice, Nude / Modulation / Original Article / Pathogenesis / Patients / PD-L1/STAT1 / Polymerase chain reaction / Prognosis / Proteins / Signal Transduction / STAT1 Transcription Factor - metabolism / Therapeutic targets / Transcription factors / Tumor microenvironment / Tumorigenesis / Tumors / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - immunology / Uterine Cervical Neoplasms - metabolism / Uterine Cervical Neoplasms - pathology / Xenografts / Xenotransplantation