Related Experiment Video
Updated: Feb 12, 2026
The Cultivation, Growth, and Viability of Lactic Acid Bacteria: A Quality Control Perspective
Published on: June 16, 2022
Harnessing tumor acidity: innovative lactic acid-responsive promoter enables precision control of CAR-T cell activity
Meiqi Feng1, Linxia Zhang1, Qibin Liao2,3
1Institutes 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.
Background:
The 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.
Methods:
We 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.
Results:
Our 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.
Conclusions:
Our 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.
Insights
Engineered CAR-T cells use lactic acid to target tumors, improving efficacy and safety. This novel approach enhances cancer immunotherapy by controlling activity in acidic tumor environments.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Solid tumors exhibit an acidic tumor microenvironment (TME) due to lactic acid accumulation.
- This acidity impairs chimeric antigen receptor-T (CAR-T) cell function and increases on-target, off-tumor toxicity (OTOT).
Purpose of the Study:
- Develop a novel CAR-T technology using lactic acid as a tumor-specific trigger.
- Achieve precise control of CAR activity for enhanced anti-tumor efficacy and reduced OTOT.
Main Methods:
- Engineered a lactic acid-responsive promoter (LARP) and integrated it into HER2-targeting CAR-T cells.
- Quantified CAR expression, assessed in vitro cytotoxicity, and evaluated in vivo anti-tumor efficacy and OTOT in a humanized mouse model.
Main Results:
- LARP successfully increased CAR expression in acidic conditions, enhancing in vitro tumor killing.
- In vivo, LAR CAR-T cells demonstrated comparable tumor eradication with significantly improved safety profiles, including absent hepatotoxicity and minimal off-target toxicity.
Conclusions:
- The LARP strategy precisely controls CAR-T cell activity in acidic TME, overcoming efficacy and safety barriers.
- This lactic acid-sensing CAR-T platform offers a clinically translatable approach for solid tumor immunotherapy.
Related Concept Videos
03:42Amino acids
03:38Polyprotic Acids
02:43Nucleic Acids
DNA and RNA
The two main types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is the genetic material in all living organisms, ranging from single-celled bacteria to multicellular mammals. It is in the nucleus of eukaryotes and in the organelles, chloroplasts, and mitochondria. In prokaryotes,...
02:43Nucleic acids
DNA and RNA
The two main types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA is the genetic material in all living organisms, ranging from single-celled bacteria to multicellular mammals. It is in the nucleus of eukaryotes and in the organelles, chloroplasts, and mitochondria. In prokaryotes,...
03:27Mixtures of Acids
A Mixture of a Strong Acid and a Weak Acid
In a mixture of a strong acid and a weak acid, the strong acid dissociates completely and becomes a source of almost all the hydronium ions...
01:21Acidity of Carboxylic Acids