Evidence map›Paper›PMID 41526167›Full record

ArticleJournal for immunotherapy of cancer2026

Fully human anti-B7-H4 antibody induces lysosome-dependent ferroptosis to reverse primary resistance to PD-1 blockade.

Renlu Zhang, Yang Wang, Yue Wu, Bingyu Zheng, Qiumei Cao, Yunhan Chen, Zhengyun Cao, Yanyang Zhu, Linlin Zhou, Qiuyu Zhang

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

3 citing papers in PubMed.

  1. The role of lysosome-dependent cell death in cancer.Apoptosis : an international journal on programmed cell death · 2026
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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

10 authors.

Renlu ZhangInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Yang WangInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Yue WuInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Bingyu ZhengInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Qiumei CaoInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Yunhan ChenInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Zhengyun CaoInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Yanyang ZhuInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Linlin ZhouInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
Qiuyu ZhangInstitute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China qiuyu.zhang@fjmu.edu.cn.ORCID http://orcid.org/0000-0003-4081-7480

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundAlthough immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with certain cancers, their efficacy is largely confined to "hot" tumors characterized by robust infiltration of tumor-specific CD8

methodsWe evaluated the association between B7-H4 expression and clinical outcomes in ICI-treated patients using public immunotherapy datasets. The role of B7-H4 in mediating resistance to PD-1 therapy was examined in mouse tumor models. A fully human anti-B7-H4 monoclonal antibody (clone A8) was generated via phage display screening from a non-immunized human single-chain variable fragment library. In vitro assays assessed antibody-induced tumor cell death and immune activation, while in vivo efficacy was tested in MC38-mH4 and SKOV3-hH4 tumor models, as well as human colorectal cancer organoids. Statistical analyses included Student's t-test, one-way analysis of variance, and Kaplan-Meier survival analysis, with p<0.05 considered significant.

resultsHigh B7-H4 expression was associated with inferior prognosis in patients receiving ICI therapy. In MC38-mH4 tumors, B7-H4 expression conferred resistance to anti-PD-1 treatment. We identified A8, a novel antibody targeting the IgV-like domain of B7-H4, with cross-reactivity to both human and mouse B7-H4. A8-hIgG1 and its Fab fragment induced dynamin-dependent endocytosis of B7-H4, resulting in lysosomal accumulation, altered lysosomal membrane permeabilization and intracellular acidification, ultimately triggering ferroptosis, a form of immunogenic cell death. A8 binding was enhanced under acidic conditions (pH 5.5), promoting lysosome-dependent degradation of B7-H4. A8-induced ferroptosis enhanced dendritic cell maturation, macrophage phagocytosis, and T cell activation. In vivo, A8 promoted CD8

conclusionsOur study identifies a novel mechanism by which a fully human anti-B7-H4 antibody induces lysosome-dependent immunogenic tumor cell death. These findings support the therapeutic potential of A8 as a single agent or in combination with PD-1 blockade to overcome immune resistance in B7-H4-expressing "cold" tumors.

Indexed as

Antibodies, MonoclonalAntineoplastic Agents, ImmunologicalDrug Resistance, NeoplasmFerroptosisImmune Checkpoint InhibitorsLysosomesProgrammed Cell Death 1 ReceptorV-Set Domain-Containing T-Cell Activation Inhibitor 1AnimalsCell Line, TumorFemaleHumansMiceTumor MicroenvironmentAntibodies, MonoclonalAntineoplastic Agents, ImmunologicalImmune Checkpoint InhibitorsPDCD1 protein, humanProgrammed Cell Death 1 ReceptorV-Set Domain-Containing T-Cell Activation Inhibitor 1VTCN1 protein, humanCombination therapyImmune Checkpoint InhibitorMonoclonal antibodyT cellTumor microenvironment - TME

Identifiers

PMID41526167
PMCPMC12815153

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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.