Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

Abstract

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.

Keywords: T cells; acidic TME; extracellular pH; immunotherapy resistance; lactate metabolism; tumor microenvironment (TME).

Figure 1

Lactate production in proliferating and tumor cells expressing GPR81. The metabolic process in rapidly dividing tumor cells that express GPR81 results in the generation of lactate and consequent acidosis in the surrounding tumor microenvironment. Tumor cells, because of their rapid pace of growth, primarily depend on glycolysis for generating energy, even when oxygen is available (known as the Warburg effect). This metabolic transition leads to the conversion of glucose into pyruvate, which is then converted into lactate by the action of lactate dehydrogenase (LDH). The surplus lactate generated is expelled from the cell via monocarboxylate transporters (MCTs), resulting in acidic extracellular surroundings. The figure was created using BioRender.com.

Figure 2

Tumor-specific T cell induction and activation. This diagram depicts the fundamental mechanisms involved in the activation and operation of tumor-specific T cells within the TME. Antigen presentation by dendritic cells (DCs), which relocate from the tumor to the lymph nodes. In this context, DCs stimulate the activation of T cells, namely cytotoxic T lymphocytes (CTLs), by presenting antigens derived from tumors. Inducing CTL activity results in the apoptosis of tumor cells, which is carried out by CTLs. Suppressive functions of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in regulating immunological responses. The intricate interaction within the TME ultimately affects the effectiveness of the immune response against the tumor. The figure was drawn and modified by BioRender.com, 6 November 2024.

Figure 3

Effect of low pH on activated T cell and tumor cell interactions. Elevated lactate levels from tumor cells hinder T cell activation, proliferative capacity, and cytotoxic effect, diminishing their capacity to specifically target and eliminate tumor cells. Acidic environments inhibit T cell activity, which suppresses T cells’ anti-tumor response and lets tumor cells avoid immune monitoring and multiply. This indicates that acidosis promotes tumor survival, proliferation, and resistance to immunotherapy. The figure was created using BioRender.com.

Figure 4

The role of lactic acid in macrophages during inflammation as a signaling molecule. Lactic acid communicates with macrophages by two main mechanisms: transporter-mediated (McT) or sodium-dependent co-transport (SLC5A8, SLC5A12), and receptor-mediated (GPR). Lactic acid employs a negative feedback mechanism to impede glycolysis. Lactic acid stimulates the Wnt/β-catenin and Yap/Taz signaling pathways and suppresses the NF-κB signaling pathway via binding to GPR receptors on the cell membrane. Lactic acid penetrates the nucleus and attaches to histone lysine residues, so directly stimulates the activation of M2 genes by histone lactylation. The figure was created using BioRender.com.

Figure 5

Effect of targeting extracellular tumor pH on immunotherapy efficacy in a triple-negative breast cancer (TNBC) mouse model. Breast cancer cells release lactate and protons to maintain intracellular homeostasis, resulting in an acidic pHe in the tumor microenvironment. Oral administration of sodium bicarbonate or sodium bicarbonate plus anti-PD-L1 combination enhances anti-tumor immunity in TNBC. Treatment leads to tumor growth inhibition and increased survival time, indicating the potential of pH-neutralizers in improving cancer immunotherapy. This combination therapy demonstrates significant impact, offering a powerful approach to personalized medicine. The figure was created using BioRender.com.