Acidosis Drives Metabolic Rewiring in Tumors, Promoting Cancer Cell Survival Under Stress

A new study reveals that acidosis—a common but often overlooked feature of the tumor microenvironment—plays a central role in orchestrating how cancer cells adapt to harsh metabolic conditions. Published by Groessl et al. in Science, the research employs a comprehensive CRISPR screening approach to uncover how tumor cells reshape energy metabolism in response to environmental stress, particularly in pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive and metabolically demanding malignancies.

While previous research has examined the effects of individual metabolic stressors—such as nutrient deprivation or hypoxia—on cancer cells in isolation, this study is among the first to explore how cells respond to the complex, overlapping stressors they encounter within actual tumors. Using a sequential genome-wide CRISPR screen, the researchers identified genes essential for cancer cell fitness under defined metabolic conditions in vitro and then tested their relevance in vivo, within mouse models of PDAC.

What emerged was a striking insight: the dominant environmental driver of metabolic adaptation in tumors was not nutrient starvation or oxygen deprivation, but acidosis—the acidic conditions created by lactic acid buildup in the tumor microenvironment. This low-pH state proved to be a master regulator of tumor bioenergetics.

Mechanistically, the study found that acidosis suppresses the activity of extracellular signal–regulated kinase (ERK), a key oncogenic signaling pathway frequently upregulated in cancer. This ERK inhibition, in turn, prevents the activation of dynamin-related protein 1 (DRP1), a mitochondrial fission factor. Without DRP1-mediated fragmentation, mitochondria remain in a fused state, forming extended networks that enhance the cell’s capacity for oxidative phosphorylation.

This metabolic shift—from glycolysis to mitochondrial respiration—allows cancer cells to utilize a broader range of bioenergetic substrates, granting them flexibility and resilience under nutrient-limited conditions. These adaptations were shown to be critical for tumor growth; genetically forcing mitochondria into a fragmented state blocked the benefits of acidosis-driven metabolic rewiring and suppressed cancer cell proliferation in acidic tumors.

Interestingly, when cells were exposed to combinations of metabolic stressors, acidosis consistently overrode the effects of starvation, underscoring its dominant role in shaping tumor metabolism. In cell culture, lactic acid exposure was sufficient to recapitulate the metabolic adaptations observed in vivo, suggesting that the acidic environment itself—not merely the buildup of specific metabolites—was the key factor driving change.

This discovery not only refines our understanding of tumor metabolism but also reconciles conflicting models about the role of mitochondrial dynamics in cancer. While mitochondrial fragmentation has often been viewed as a hallmark of oncogenic signaling, these new findings suggest that it is a reversible process, sensitive to extracellular pH and capable of being overridden in favor of more energy-efficient fused networks under acidic conditions.

The implications extend beyond basic biology. Acidosis-induced suppression of ERK activity and subsequent mitochondrial fusion may represent a previously unrecognized resistance mechanism to targeted therapies. Moreover, the study provides a blueprint for future metabolic interventions, particularly in cancers like PDAC that are defined by their adaptability and resistance to conventional therapies.

As metabolic targeting gains traction in oncology, understanding the environmental cues that guide energy metabolism becomes essential. This study identifies tumor acidosis not merely as a by-product of glycolytic metabolism but as a central orchestrator of metabolic resilience—one that helps cancer cells withstand the very stress conditions that are lethal to normal tissue.

The findings pave the way for potential therapeutic strategies that disrupt these acidosis-driven adaptations, either by altering tumor pH or targeting the molecular pathways that allow cells to switch metabolic gears. In the ongoing effort to outmaneuver cancer’s adaptability, understanding its environmental choreography may prove just as important as understanding its genetic drivers.