Evidence map›Paper›PMID 42310180›Full record

ArticleGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association2026

CXCL12 upregulates PD-L1 expression and promotes M2 polarisation of tumour-associated macrophages to confer anti-PD-1 resistance in gastric cancer.

Chao Wu, Boya Li, Huiling Li, Panjie Zhu, Yichen Wang, Xiaoxi Li, Yingnan Feng, Li Zhang, Zizhao Cheng, Dan Gao and 2 more

Abstract read
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In one paragraph

Article in Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Chao Wu *Department of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Boya Li *Department of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Huiling Li *Department of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Panjie ZhuDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Yichen WangDepartment of Clinical Pharmacology, Chinese PLA General Hospital, Beijing, 100141, China.
Xiaoxi LiDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Yingnan FengDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Li ZhangDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Zizhao ChengDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Dan GaoDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
Lan ZhangDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China. zhanglan@xwhosp.org.
Xianzhe DongDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China. dongxianzhe@xwhosp.org.

Funding

Beijing Hospitals Authority Youth Programme QML20230811National Natural Science Foundation of China 81773778National Natural Science Foundation of China 82271765Talent Project established by Chinese Pharmaceutical Association Hospital Pharmacy department CPA-Z05-ZC-2023-003Youth Programme of Xuanwu Hospital of Capital Medical University QNPY202418Youth Program of Beijing Municipal TCM Science and Technology Development Fund BJZYQN-2025-21
6 · The paper itself

Abstract

objectiveImmunotherapy offers promise for gastric cancer (GC) patients, yet its efficacy is substantially limited by high rates of treatment resistance, the mechanisms of which remain incompletely characterised. We aimed to delineate the role and mechanistic basis of CXCL12 in conferring anti-PD-1 resistance in GC.

methodsAn anti-PD-1-resistant GC mouse model was established through chronic anti-PD-1 induction and in vivo tumour tissue passaging. Human and murine GC cell lines stably overexpressing CXCL12 (OE-CXCL12) were generated via lentiviral transduction to construct corresponding OE-CXCL12 GC mouse models. Single-cell transcriptomics analysed the tumour microenvironment (TME) in anti-PD-1-resistant GC. Molecular docking and Drug Affinity Responsive Target Stability (DARTS) assays predicted and validated ligand-receptor binding, respectively. RNA or protein expression of specific molecules was quantified by RT-qPCR, ELISA, immunofluorescence, and western blotting.

resultsAnti-PD-1-resistant GC models showed upregulated CXCL12, PD-L1, and CD206 expression with unchanged PD-1. OE-CXCL12 reduced anti-PD-1 sensitivity, elevated M2-TAM infiltration and TGF-β, IL-10, IL-4 levels in TME, reduced M1-TAM and CD8⁺ T cell infiltration and IL-12 level, with differentially expressed genes enriched in HIF-1, PD-L1/PD-1 checkpoint, and PI3K/AKT signalling pathways. M2-TAM-conditioned medium elevated SOX2, OCT-4, NANOG in GC cells. Mechanistically, CXCL12 binds CXCR4 to activate PI3K/AKT/HIF-1α, promoting PD-L1 expression and M2-TAM polarisation. CXCL12 inhibition recovered anti-PD-1 efficacy.

conclusionsThis identifies CXCL12 as a novel anti-PD-1 resistance gene in GC, with the CXCL12/CXCR4/PI3K/AKT/HIF-1α axis induces anti-PD-1 tolerance through a dual-pathway mechanism of promoting PD-L1 expression and M2-TAM polarisation, providing potential therapeutic strategies to prevent and reverse anti-PD-1 resistance in GC.

Indexed as

B7-H1 AntigenChemokine CXCL12Drug Resistance, NeoplasmImmune Checkpoint InhibitorsStomach NeoplasmsTumor-Associated MacrophagesAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceProgrammed Cell Death 1 ReceptorSignal TransductionTumor MicroenvironmentUp-RegulationB7-H1 AntigenCD274 protein, humanChemokine CXCL12CXCL12 protein, humanCxcl12 protein, mouseImmune Checkpoint InhibitorsProgrammed Cell Death 1 ReceptorCXCL12Gastric cancerImmunotherapyPD-1Tumor associated macrophages

Identifiers

PMID42310180

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.