A growing body of scientific insight is transforming how cancer treatment resistance is understood, highlighting a powerful cellular process known as lactylation as a central driver of disease progression and therapeutic failure. This emerging perspective is reshaping the landscape of oncology, pointing to new opportunities for more precise and effective interventions.
Cancer remains one of the most pressing global health challenges, with many patients experiencing relapse despite advances in radiotherapy, chemotherapy, targeted therapy, and immunotherapy. A key factor behind this challenge is the ability of tumor cells to adapt and survive under treatment pressure. At the center of this adaptability is metabolic reprogramming, where cancer cells shift their energy production to generate large amounts of lactate, once thought to be merely a byproduct.
This metabolic shift fuels lactylation, a process that modifies proteins and alters how genes are expressed. By acting as a bridge between metabolism and gene regulation, lactylation enables cancer cells to rapidly adjust to hostile conditions. The diagram on page 3 illustrates how lactate serves not only as an energy intermediate but also as a signaling molecule that drives widespread cellular changes, including gene activation and protein modification.
The consequences of this process are far-reaching. Lactylation strengthens the ability of tumor cells to repair damage, evade cell death, and maintain cancer stemness, a state associated with aggressive growth and recurrence. It also contributes to the formation of an immunosuppressive tumor microenvironment, limiting the effectiveness of immune-based treatments. The visual summary on page 6 highlights how these mechanisms collectively support resistance across multiple treatment types by enhancing DNA repair pathways and blocking ferroptosis, a form of cell death critical for eliminating cancer cells.
Importantly, lactylation operates through interconnected feedback systems that reinforce cancer survival. These loops sustain high levels of metabolic activity and continuously amplify resistance mechanisms, making tumors more difficult to treat over time.
New therapeutic strategies are now focusing on disrupting these pathways. Approaches include reducing lactate production, targeting enzymes that regulate lactylation, and directly interfering with modified proteins that drive resistance. These strategies aim to restore treatment sensitivity and improve outcomes by addressing the underlying biology of tumor persistence.
While challenges remain due to the complexity and variability of these processes, the identification of lactylation as a key regulatory mechanism marks a significant step forward. By targeting the intersection of metabolism and gene control, this evolving understanding opens the door to a new generation of precision cancer therapies designed to overcome resistance and improve patient care.
# # # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus CiteScore: 8.4 |Impact Factor: 9.4
# # # # # #
More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.cn
X (formerly twitter): @GenesNDiseases (https://x.com/GenesNDiseases)
# # # # # #
Reference
Wanghao Zhang, Guanglong Huang, Woheng Tang, Jiaxian Li, Jingxian Chen, Yaojiang Feng, Kaichen Li, Can Pan, Shunshen Li, Huayang Zhang, Rongxu Ye, Hao Long, Guo-zhong Yi, Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities, Genes & Diseases,
Volume 13, Issue 4, 2026, 101935, https://doi.org/10.1016/j.gendis.2025.101935

Funding
National Natural Science Foundation of China 82272636
National Natural Science Foundation of China 82473161
Guangdong Science and Technology Department (China) 2024A1515011749
Guangdong Science and Technology Department (China) 2023A1515012382)