Tumour Glycolysis Drives Vascular Dysfunction and Immunotherapy Resistance, Preclinical Study Shows

Immune checkpoint inhibitors (search)Search drug have reshaped the oncology landscape, yet durable responses remain confined to a minority of patients. A new preprint from Serganova, Colombo and colleagues now identifies tumour glycolytic capacity as a critical determinant of vascular integrity and immunotherapy responsiveness, offering mechanistic insight into why many cancers evade immune-mediated destruction.

The study, posted on a preprint server and not yet peer reviewed, demonstrates that dampening glycolysis in tumour cells produces far-reaching effects on the tumour microenvironment—normalizing the chaotic vasculature that characteristically impedes T cell infiltration and function.

Glycolysis inhibition reshapes the tumour vascular landscape

Working with highly glycolytic B16F10 melanoma (search)Search disease and 4T1 triple-negative breast cancer (search)Search disease models, the researchers knocked down lactate dehydrogenase A (LDHA (search)Search target), a key enzyme in the glycolytic pathway. Reducing LDHA expression lowered overall tumour glycolysis and produced striking vascular changes: tumour blood vessels became more normalized, levels of lymphangiogenic factors increased, and—critically—the abundance of high endothelial venules (HEVs) rose substantially.

HEVs are specialized blood vessels that serve as portals for lymphocyte entry into tissues. Their presence in tumours has been linked to improved immune infiltration and better clinical outcomes. The observed increase in HEVs following glycolysis reduction suggests a previously underappreciated link between cancer cell metabolism and the structural features that govern immune access to the tumour bed.

Enhanced T cell egress and anti-tumour immunity

The vascular remodelling triggered by LDHA (search)Search target knockdown had functional immunological consequences. The study found that tumour-specific CD8+ T cells showed enhanced egress from the tumour to draining lymph nodes. This trafficking pattern implies that a more normalized vasculature facilitates productive immune surveillance rather than trapping T cells in a hostile, disorganized microenvironment.

These findings align with the broader observation that aerobic glycolysis—the Warburg effect—not only fuels tumour proliferation but also drives angiogenesis, generating the leaky, tortuous vessels that impair effective T cell infiltration.

Human cancer data reinforce preclinical findings

To assess the clinical relevance of their observations, the authors analyzed transcriptomic data from several human cancer types. Glycolytic gene expression signatures consistently correlated positively with markers of neo-angiogenesis and negatively with both HEV abundance and immune cytolytic activity scores. This inverse relationship between tumour glycolysis and immune-mediated killing capacity underscores the translational potential of targeting metabolic pathways to enhance immunotherapy.

Metabolic context shapes T cell functionality

The study's findings resonate with complementary research on how the tumour microenvironment shapes immune cell behaviour. A separate investigation by the Immunology Group at Pompeu Fabra University, in collaboration with the Hospital del Mar Research Institute, revealed that tumour-infiltrating lymphocytes (TILs) exhibit distinct functional and metabolic profiles depending on their proximity to the blood supply.

"Lymphocytes with greater access can obtain nutrients such as glucose more easily and be more active biosynthetically," said José Aramburu, study co-director and member of the UPF Immunology Group. However, lymphocytes situated in nutrient-poor, poorly vascularized regions displayed a surprising resilience. "These lymphocytes can achieve substantial activation and might be able to maintain sufficient energy at very low glucose levels," explained Cristina López-Rodríguez, who co-led the study.

Notably, T cells in adverse microenvironments showed lower expression of immune markers associated with inhibition and exhaustion, "which suggests that they could play a different role in the anti-tumour response," López-Rodríguez added.

Therapeutic implications

Together, these findings point toward tumour glycolysis as a master regulator of the vascular-immune interface. By driving aberrant angiogenesis and suppressing HEV formation, high glycolytic activity creates a structural barrier to effective immunotherapy. Strategies that moderate tumour glycolysis—whether through direct enzyme inhibition or metabolic reprogramming—could potentially convert immunologically "cold" tumours into "hot" ones by restoring vascular normalcy and facilitating T cell access.

"In tumours, the immune response faces strong opposition from the microenvironment," Aramburu stated. "A better understanding of how the location of lymphocytes within this heterogeneous mass determines their metabolic strengths and vulnerabilities can help develop more effective immunotherapies."

The preprint from Serganova, Colombo et al. awaits peer review, but its convergence with independent findings on TIL metabolic adaptation strengthens the case that tumour metabolism represents a tractable axis for improving immunotherapy outcomes across multiple cancer types.