Evidence map›Paper›PMID 41667151›Full record

ArticleJournal for immunotherapy of cancer2026

Harnessing tumor acidity: innovative lactic acid-responsive promoter enables precision control of CAR-T cell activity in solid tumors.

Meiqi Feng, Linxia Zhang, Qibin Liao, Lingyan Zhu, Nairong Zheng, Yangyang Hu, Cuisong Zhu, Yunyu Mao, Ying Xue, Ai Xia and 4 more

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. Review
  2. Review
  3. 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

14 authors.

Meiqi FengInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Linxia ZhangInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Qibin LiaoState Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Lingyan ZhuDepartment of Pathology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China.
Nairong ZhengInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Yangyang HuInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Cuisong ZhuInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Yunyu MaoInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Ying XueInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Ai XiaInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Chen ZhaoInstitutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Xiangqing DingSinobay Biotechnology Co., Ltd, Shanghai, China.
Xiaoyan Zhang *Institutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Jianqing Xu *Institutes of Biomedical Sciences & Clinical Center of Biotherapy at Zhongshan Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China xujianqing@fudan.edu.cn.ORCID http://orcid.org/0000-0003-0896-9273

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundThe acidic tumor microenvironment (TME) in solid tumors, driven by abnormal metabolism and lactic acid accumulation, suppresses chimeric antigen receptor-T (CAR-T) cell efficacy while posing safety risks from on-target, off-tumor toxicity (OTOT). This study aims to develop a novel CAR-T technology that leverages lactic acid as a tumor-specific trigger to achieve precise control of CAR activity. The objective is to enable adaptation to the acidic TME while maintaining robust anti-tumor efficacy and mitigating OTOT.

methodsWe engineered a lactic acid-responsive promoter (LARP) using RNA sequencing-identified lactic acid-sensitive genes. This promoter was integrated into HER2-targeting CAR to construct LAR CAR-T cells. CAR expression dynamics under acidic vs neutral conditions were quantified via flow cytometry. Phenotypic profiling (memory markers), in vitro cytotoxicity, and cytokine secretion were assessed. In vivo OTOT was evaluated in our previously constructed humanized HER2 mice, while anti-tumor efficacy and OTOT were further tested in this mouse model bearing tumors.

resultsOur findings demonstrate that the LARP responds to lactic acid, leading to increased CAR expression in acidic conditions. The ex vivo-expanded LAR CAR-T cells exhibited an enhanced memory phenotype and superior tumor-killing capacity in vitro under acidity. In vivo, LAR CAR-T cells achieved tumor eradication comparable to conventional CAR-T cells and exhibited significantly enhanced safety profiles, characterized by the absence of acute hepatotoxicity and minimal off-target organ toxicity.

conclusionsOur LARP strategy exploits tumor acidity as a precise low/high switch for CAR-T cells. By restricting potent CAR expression to the acidic TME while minimizing activity in normal tissues, LAR CAR-T overcomes key barriers of efficacy and OTOT in solid tumors. This lactic acid-sensing paradigm offers a clinically translatable platform for precise immunotherapy.

Indexed as

Immunotherapy, AdoptiveLactic AcidNeoplasmsPromoter Regions, GeneticReceptors, Chimeric AntigenAnimalsCell Line, TumorFemaleHumansMiceTumor MicroenvironmentXenograft Model Antitumor AssaysLactic AcidReceptors, Chimeric AntigenChimeric antigen receptor - CARImmunotherapySolid tumorTumor microenvironment - TME

Identifiers

PMID41667151
PMCPMC12911723

What Socratic holds

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LicenceCC BY-NC
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Registered trials

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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 Socratic graph.