BioAcyl Corp
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Rahman, M. A., Yadab, M. K., & Ali, M. M. (2024). Emerging role of extracellular ph in tumor microenvironment as a therapeutic target for cancer immunotherapy. Cells, 13(1924). Added by: Dr. Enrique Feoli (13/09/2025, 01:59) Last edited by: Dr. Enrique Feoli (13/09/2025, 02:04) |
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| Resource type: Journal Article DOI: 10.3390/cells13221924 ID no. (ISBN etc.): 2073-4409 BibTeX citation key: Rahman2024 View all bibliographic details  |
Categories: BioAcyl Corp Subcategories: Perivascular microenvironment Creators: Ali, Rahman, Yadab Collection: Cells |
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| Abstract |
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Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a “protective shield,” neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.
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Buffering agents could counteract the acidic tumor environment, hence creating a more conducive setting for immune cells to operate effectively [105]. Our recent study found that administering sodium bicarbonate (NaHCO3) orally improved the effectiveness of anti-PD-L1 antibody treatment in combating tumors [92]. This was demonstrated by the observed induction of anti-tumor immunity, suppression of tumor development, and enhancement of survival in the 4T1-Luc breast cancer model. Our observation revealed that NaHCO3 caused a rise in the pHe in tumor tissues in living organisms. This increase in pH was associated with an augmentation in the infiltration and activation of T cells, as well as an elevation in the mRNA expression of IFN-γ, IL-2, and IL-12p40 in tumor tissues. Furthermore, there was an augmentation in the activation of T cells in the lymph nodes that drain the tumor. Significantly, these effects were enhanced when NaHCO3 was paired with anti-PD-L1 therapy. Under this condition, the presence of acidity in the external environment greatly enhanced the expression of PD-L1. The results indicate that using NaHCO3 as a therapy to increase alkalinity shows promise as a new way to modulate the immune response in the TME (Figure 5). Our hypothesis is that the administration of NaHCO3 can enhance the anti-cancer effects of anti-PD-L1 therapy specifically in breast cancer. This combined treatment has the potential to greatly influence future immunotherapeutic methods for triple-negative breast cancer (TNBC) by offering a strong customized medicine approach. The findings of our study have significant implications for enhancing the outcomes of patients with TNBC.
 Added by: Dr. Enrique Feoli Last edited by: Dr. Enrique Feoli |