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Novel therapeutic strategies targeting the tumor microenvironment have become a research focus in the field of biomedicine. In this study, we developed a smart small-molecule probe, TZ2, featuring pH\/GSH dual-responsive characteristics. TZ2 exhibits a unique pH-dependent reaction mechanism: GSH is preferentially covalently modified with maleimide groups in acidic microenvironments (pH &lt; 7), while specifically activating nucleophilic substitutions under alkaline conditions (pH &gt; 7). It is worth noting that TZ2 effectively eliminates intracellular glutathione (GSH) in a time and concentration-dependent manner, demonstrating significant GSH depletion ability in various tumor cell lines. Pharmacodynamic studies have shown that TZ2 not only inhibits the cell cycle by regulating the expression of cell cycle-related proteins, but also effectively suppresses the cloning ability of cancer cells. Furthermore, TZ2 significantly increases the sensitivity of drug-resistant cancer cells to cisplatin. By integrating microenvironment modulation, real-time monitoring, and synergistic therapy, TZ2 provides a novel molecular tool and theoretical basis for tumor theranostics integration.<\/jats:p>","DOI":"10.3390\/molecules30153081","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T10:49:17Z","timestamp":1753267757000},"page":"3081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A pH-Sensitive Glutathione Responsive Small-Molecule Probe TZ2 Sensitizes Lung Cancer Cells to Chemotherapy by Targeting Tumor Microenvironment"],"prefix":"10.3390","volume":"30","author":[{"given":"Changle","family":"Zhong","sequence":"first","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghan","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanhao","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintong","family":"You","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7998-2195","authenticated-orcid":false,"given":"Guohai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107753","DOI":"10.1016\/j.pharmthera.2020.107753","article-title":"Tumor microenvironment as a therapeutic target in cancer","volume":"221","author":"Xiao","year":"2021","journal-title":"Pharmacol. 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