文献类型：期刊文献

英文题名：Targeting PPP1R14B overcomes immunotherapy resistance in prostate cancer by restoring CD8+T-cell infiltration via the Nrf2/CX3CL1 axis

作者：Yang, Jie[1];Zhou, Chuan[1];Zhang, Wenbo[2];He, Han[1];Wang, Jia[2];Wang, Chao[1];Zhou, Fenghai[1,2,3,4]

第一作者：Yang, Jie

通信作者：Zhou, FH[1]

机构：[1]Lanzhou Univ, Sch Clin Med 1, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou, Peoples R China;[3]Gansu Prov Hosp, Dept Urol, Lanzhou, Peoples R China;[4]Sichuan Taikang Hosp, Dept Urol, Chengdu, Peoples R China

第一机构：Lanzhou Univ, Sch Clin Med 1, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Sch Clin Med 1, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China.

年份：2026

外文期刊名：JOURNAL OF PATHOLOGY

收录：;Scopus(收录号：2-s2.0-105051432251);WOS:【SCI-EXPANDED(收录号:WOS:001881674600001)】；

基金：This research was supported by Natural Science Foundation of Gansu Province 'excellent doctoral program' (No. 24JRRA613) and Lanzhou University First Hospital fund (No. ldyyyn2023-33); Innovation Fund Project for University Teachers of Gansu Province (2026B-006).

语种：英文

外文关键词：prostate cancer; lymphocyte chemotaxis; CX3CL1; immunosuppression; tumor microenvironment; immunotherapy resistance; Nrf2/CX3CL1 axis; chimeric antigen receptor T cell

摘要：Prostate cancer (PCa) is typically immunologically 'cold', which limits the effectiveness of immunotherapy, and this study sought to identify key genes driving this immunosuppressive phenotype and assess their therapeutic potential. We analyzed transcriptomic data from 487 TCGA-PRAD patients and three Gene Expression Omnibus datasets; weighted gene co-expression network analysis was used to identify cancer-related genes, TIMER to evaluate their influence on the tumor microenvironment, and findings were validated via flow cytometry on 32 clinical PCa specimens. Immunoblotting measured Nrf2, p-AKT, and p-GSK-3 beta levels, while ChIP-qPCR assessed Nrf2 and RNA polymerase II binding to the CX3CL1 promoter, and functional studies were conducted in allograft and xenograft mouse models using GapmeR antisense oligonucleotides combined with anti-PD-1 antibodies or PSMA-targeted CAR-T cells. We found PPP1R14B (PP1 regulatory inhibitor subunit 14B) was overexpressed in PCa and associated with poor prognosis, promoting PCa cell proliferation, suppressing apoptosis, and correlating with increased tumor purity but reduced CD8+ T-cell infiltration; mechanistically, CX3CL1 was regulated by Nrf2 and PPP1R14B elevated p-AKT/p-GSK-3 beta to stabilize Nrf2, which bound the CX3CL1 promoter, suppressed its expression, and impaired CD8+ T-cell chemotaxis. GapmeR-mediated PPP1R14B knockdown suppressed tumor growth and enhanced anti-PD-1/CAR-T efficacy in mice, indicating PPP1R14B is a promising target to overcome PCa immunotherapy resistance.