{
  "abstract": "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.",
  "authors": [
    {
      "affiliations": [
        "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"
      ],
      "name": "Meiqi Feng"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Linxia Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China",
        "The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China"
      ],
      "name": "Qibin Liao"
    },
    {
      "affiliations": [
        "Department of Pathology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China"
      ],
      "name": "Lingyan Zhu"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Nairong Zheng"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Yangyang Hu"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Cuisong Zhu"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Yunyu Mao"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Ying Xue"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Ai Xia"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Chen Zhao"
    },
    {
      "affiliations": [
        "Sinobay Biotechnology Co., Ltd, Shanghai, China"
      ],
      "name": "Xiangqing Ding"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Xiaoyan Zhang"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Jianqing Xu"
    }
  ],
  "title": "Harnessing tumor acidity: innovative lactic acid-responsive promoter enables precision control of CAR-T cell activity in solid tumors",
  "uid": "af7fc91e-bbaf-5bae-8108-a46c73bab026"
}