Extracellular acidity is a common feature of many solid tumors, similar to hypoxia. Increased metabolic rates, higher glycolysis and inadequate vasculature all contribute to the accumulation of acid in the tumor microenvironment (TME). This aspect is also one of their most effective defenses.
Driven by altered metabolism and poor perfusion, the acidic TME suppresses immune cell function, promotes treatment resistance, and enables disease progression. While buffering tumor pH has shown promise in preclinical studies, translating this strategy into the clinic has proven elusive.
New preclinical data from researchers at Moffitt Cancer Center and Dyve Biosciences suggest a non-invasive, transdermal approach may finally offer a practical way to systemically modulate tumor acidity. Published in Frontiers in Immunology, a novel bicarbonate-based cream, DYV800, increased intratumoral pH, restored T cell activity, slowed tumor growth, and significantly improved survival within murine models of bladder cancer.
Acidity as an upstream driver of immune suppression
Acidosis is a near-universal hallmark of solid tumors, arising primarily from the metabolic reprogramming of cancer cells toward aerobic glycolysis, known as the Warburg effect. The resulting extracellular pH, often as low as 6.2-6.8, creates an environment that favors invasion and immune evasion while impairing normal immune surveillance.
“Tumor acidity is not just a byproduct of cancer metabolism," Ryan Beal, CEO and founder at Dyve Biosciences, told DDN. "It is part of how tumors protect themselves. Low pH suppresses T cell proliferation, trafficking, activation, cytokine production, and tumor killing. It also supports invasion, metastasis, and treatment resistance. In practical terms, acidity helps tumors spread and shuts down the immune response trying to eliminate them."
The new study provides a detailed mechanistic picture of how acidity directly compromises T cell function. In vitro experiments demonstrated that CD8+ T cells exposed to acidic conditions showed markedly reduced proliferation, impaired migration, diminished activation, and lower production of key effector cytokines. Transcriptional and metabolic profiling showed widespread suppression of pathways involved in cell division and energy production, causing activated T cells to stall early in the cell cycle.
These findings reinforce the concept of tumor acidosis as an upstream regulator of immune dysfunction — one that acts independently of canonical immune checkpoints and may limit the efficacy of immunotherapies even when tumor antigens are present.
Overcoming the limits of oral buffering
Systemic buffering using oral sodium bicarbonate has previously been shown to neutralize tumor acidity and improve antitumor immune responses in animal models, including in combination with immune checkpoint inhibitors. However, early clinical efforts have been hampered by the impractically high doses required, poor palatability, and gastrointestinal toxicity, rendering oral administration largely untenable.
DYV800 was developed to bypass these limitations. Delivered as a transdermal cream, the formulation enables systemic bicarbonate absorption without gastrointestinal exposure. In tumor-bearing mice, a single application of DYV800 alkalized urine for up to ten hours, while advanced imaging confirmed increased intratumoral pH following treatment.
“DYV800 is a proprietary transdermal sodium bicarbonate formulation designed to modulate the acidic TME through systemic absorption and interstitial buffering," said Beal. "The target is extracellular tumor acidity, which is where a great deal of the immune suppression lives."
Importantly, repeated application produced sustained elevation of tumor pH, accompanied by reduced tumor growth and improved survival. The therapy was effective whether applied directly over the tumor site or on the contralateral flank, indicating a systemic rather than purely local mechanism of action.
Restoring anti-tumor immunity in vivo
Beyond altering tumor chemistry, DYV800 produced clear immunological effects within the TME. While overall T cell numbers in tumors and peripheral tissues were unchanged, intratumoral CD8+ T cells displayed enhanced activation and effector function following treatment. These cells produced higher levels of key cytokines and showed reduced expression of exhaustion-associated markers.
Crucially, the antitumor effect of DYV800 was lost in immunodeficient mice lacking functional T cells, confirming that immune restoration — rather than a direct cytotoxic effect — underpins therapeutic efficacy. Treated tumors also contained a higher frequency of antigen-specific CD8+ T cells, with a positive correlation observed between intratumoral pH and antigen-specific T-cell activation.
Similar trends were observed in an orthotopic bladder cancer model, further supporting the relevance of transdermal buffering in anatomically and physiologically relevant settings.
Translational potential beyond bladder cancer
While the current data focus on bladder cancer, tumor acidosis is a shared feature across many solid malignancies. By targeting pH as a foundational property of the TME, DYV800 represents a mechanistically distinct approach that could complement existing immunotherapies.
Beal clarified, "We have seen activity across multiple preclinical models, including bladder, melanoma, lung, and breast. But I would not overstate that as proven across all solid tumors. The right way to say it is that DYV800 is designed to address a foundational feature shared by many solid tumors, and we are starting where we can get the clearest readout of pH shift, immune activation, and clinical signal."
The transdermal platform also carries translational credibility. Dyve Biosciences has previously demonstrated the feasibility of delivering therapeutically meaningful doses of bicarbonate through the skin in humans, with a Phase 2 trial of a related formulation in acute gouty arthritis showing clinical benefit.
By dismantling an acidic barrier that suppresses immune function, this approach offers a new way to enhance antitumor immunity — potentially as a standalone strategy or in combination with immune checkpoint inhibitors — across a broad spectrum of solid tumors.
