19 nov. 2025
Keywords
● Triple negative Breast Cancer
● B cell
● Tertiary Lymphoid structure
Main Findings
The paper shows that triple-negative breast tumors actively block B-cell infiltration and TLS formation through a metabolic barrier created by tumor-derived lactate. Even when chemokines such as CXCL13 or CCL21 are present, lactate, identified as a small, heat-stable metabolite enriched in tumor secretions, suppresses B-cell chemotaxis by rewiring their metabolism, shifting them away from mitochondrial respiration, which is essential for migration. Removing or inhibiting lactate restores B-cell trafficking from lymph nodes, and when combined with chemokine delivery and CD40 stimulation, enables robust intratumoral B-cell infiltration and mature TLS formation. Across human cancer datasets, tumors with high glycolysis (high lactate) consistently show poor B-cell infiltration and lack TLS, whereas CXCL13-high / low-glycolysis tumors are enriched for B cells and TLS, highlighting lactate as a conserved suppressor of B-cell-mediated anti-tumor immunity.
Limitations
Although this study provides compelling evidence that tumor-derived lactate blocks B-cell trafficking and TLS formation, several important limitations remain.
• The molecular mechanism through which lactate impairs B-cell migration remains unclear; although the metabolic rewiring is described, the signalling pathways connecting lactate uptake to defective motility are rather poorly explored. One way to strengthen the authors findings would be to examine CXCR5 and CCR7 expression on B cells isolated from tumors following lactate inhibition. Alternatively, the expression and activity of lactate transporters could be explored, too.
• The study would benefit from a validation in primary human B cells. Assessing how lactate affects actin polymerization and migration in human B cells would help determine whether the mechanism is conserved in humans.
• Despite discussing the link between TLS and immunotherapy response, the authors do not test whether combining lactate inhibition, chemokine delivery, and CD40 stimulation improves the efficacy of immune checkpoint inhibitors in vivo. Such an in vivo validation would add significant strength to their report.
• The effect of tumor-derived lactate on B cells within tumor-draining lymph nodes is not directly assessed. Measuring lactate levels in tumor-draining lymph nodes and non-draining lymph nodes would clarify whether the impairment is due to direct lactate drainage or indirect mechanisms. While explored in vitro, such measurements would help to bridge the authors findings into in vivo settings.
• The study shows that lactate limits B-cell egress from lymphoid tissues, but the inhibitor used (FTY720) blocks lymphocyte exit from all lymphoid organs, making it difficult to determine whether the observed effects specifically involve tumor-draining lymph nodes. A genetic conditional approach or more selective inhibition of B cell specific S1P receptors would add more detail to the authors’ report.
Significance/Novelty
The authors elegantly demonstrate lactate as a direct inhibitor of B-cell chemotaxis, demonstrating that it rewires B-cell metabolic programming in a way that blocks their ability to migrate and form TLS. While lactate has been implicated in suppressing migration of T cells and myeloid cells, it had never been shown to be the soluble factor preventing TLS formation by specifically targeting B cells. The work therefore fills a key gap by defining, for the first time, a B-cell–dependent mechanism through which tumor metabolism shapes immune exclusion.
TLS are strong predictors of immunotherapy success, yet many tumors, especially TNBC, fail to form them. Showing that lactate blockade can restore B-cell recruitment and enable TLS formation in an immune-excluded tumor provides a conceptually important and clinically relevant strategy for overcoming resistance to immune checkpoint inhibitors. This insight has broad implications for immunologists studying metabolic control of immunity and offers a promising therapeutic avenue for TNBC patients lacking effective treatment options.
Credit
Reviewed by Sara Lamorte (University of Toronto, Department of Immunology) as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.
The author declares no conflict of interest in relation to their involvement in the review.