Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors - Original Article

Sep 24, 2026

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Immune checkpoint inhibitors (ICIs) benefit only a minority of patients with triple-negative breast cancer (TNBC), making adaptive immune resistance (AIR) a key clinical problem. This study evaluates how epigenetic modulation involving ARID1A shapes AIR. Results associate low ARID1A with an immunosuppressive tumor microenvironment, promoting AIR, limiting CD8+ T-cell infiltration and activity, and enhancing PD-L1 transcriptional activation through NPM1 promoter binding and increased chromatin accessibility.

LanguageEnglish

CategoryHealthcare

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Pages24

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Abstract

Background

Abbreviations

Funding and Methods

Results

DOI: 10.1002/cac2.12465 ORIGINAL ARTICLE Low level of ARID1A contributes to adaptive immune resistance and sensitizes triple-negative breast cancer to immune checkpoint inhibitors Xin-Yu Chen1,2 Bin Li1,2 Ye Wang1,2 Juan Jin1,2 Yu Yang3 Lei-Huan Huang3 Meng-Di Yang1,2 Jian Zhang1,2 Bi-Yun Wang1, 2 Zhi-Ming Shao2,4, 5 Ting Ni3 Sheng-Lin Huang2, 6 Xi-Chun Hu1,2 Zhong-Hua Tao1,2 1 Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China 3 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, P. R. China 4 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P. R. China 5 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P. R. China 6 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China Correspondence Zhong-Hua Tao and Xi-Chun Hu, Department of Breast Cancer and Urologic Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Abstract Background: Immune checkpoint inhibitors (ICIs) shed new light on triplenegative breast cancer (TNBC), but only a minority of patients demonstrate response. Therefore, adaptive immune resistance (AIR) needs to be further defined to guide the development of ICI regimens. Abbreviations: AIR, adaptive immune resistance; ARID1A, AT-rich interaction domain 1A; ATAC, Assay for Transposase Accessible Chromatin; ATCC, American Type Culture Collection; Ate, Atezolizumab; BRG1/ SMARCA4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; ICI, immune checkpoint inhibitor; CCK-8, cell counting kit-8; ChIP, chromatin immunoprecipitation; CN, copy number; CPS, combined positive score; DFS, disease-free survival; DMEM, Dulbecco’s Modified Eagle Medium; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbent assay; ER, estrogen receptor; FPKM, fragments per kilobase million; FUSCC, Fudan University Shanghai Cancer Center; GB, granzyme B; GEO, Gene Expression Omnibus; GSEA, gene set enrichment analysis; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HRP, horseradish peroxidase; Hu-PBMC, human peripheral blood mononuclear cell; IFN, interferon; IHC, immunohistochemistry staining; IL, interleukin; ko, knockout; MACS, Model-based Analysis of ChIP-Seq; min, minute; nc, negative control; NPM1, nucleophosmin 1; oe, overexpression; OS, overall survival; PBS, phosphate buffer saline; pCR, pathological complete response; PD-1, programmed cell death-1; PD-L1, programmed cell death 1 ligand-1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; Pla, placebo; PMA, phorbol 12-myristate 13-acetate; PTEN, phosphatase and tensin homolog; PFS, progression-free survival; RPMI, Roswell Park Memorial Institute; s, second; sgRNA, small guide RNA; shRNA, short hairpin RNA; SWI/SNF, switch/sucrose non-fermentable; TBST, tris buffered saline with Tween-20; TCGA, The Cancer Genome Atlas; TIL, tumor-infiltrating lymphocyte; TIME, tumor immune microenvironment; TMA, tissue microarray; TNBC, triple-negative breast cancer; TPS, tumor proportion score.; UCSC, University of California Santa Cruz. Xin-Yu Chen and Bin Li contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or ada

FAQs

Why is adaptive immune resistance (AIR) important in triple-negative breast cancer?

ICIs show benefit in only a minority of TNBC patients, so AIR must be better defined to guide development of ICI regimens.

How does low ARID1A expression affect the tumor immune microenvironment?

Low ARID1A in TNBC promotes an immunosuppressive microenvironment that enhances AIR and inhibits CD8+ T-cell infiltration and activity while increasing PD-L1 via transcriptional activation.

What mechanism links ARID1A to PD-L1 regulation?

ARID1A does not directly regulate PD-L1 expression; it directly binds the NPM1 promoter, where low ARID1A increases NPM1 chromatin accessibility and gene expression to further activate PD-L1 transcription.

Sep 24, 2026

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