The impact of metabolic reprogramming on tertiary lymphoid structure formation: enhancing cancer immunotherapy

Abstract

Background: Cancer immunotherapy has achieved unprecedented success in the field of cancer therapy. However, its potential is constrained by a low therapeutic response rate.

Main body: Tertiary lymphoid structure (TLS) plays a crucial role in antitumor immunity and is associated with a good prognosis. Metabolic reprogramming, as a hallmark of the tumor microenvironment, can influence tumor immunity and promote the formation of follicular helper T cells and germinal centers. However, many current studies focus on the correlation between metabolism and TLS formation factors, and there is insufficient direct evidence to suggest that metabolism drives TLS formation. This review provided a comprehensive summary of the relationship between metabolism and TLS formation, highlighting glucose metabolism, lipid metabolism, amino acid metabolism, and vitamin metabolism.

Conclusions: In the future, an in-depth exploration of how metabolism affects cell interactions and the role of microorganisms in TLS will significantly advance our understanding of metabolism-enhanced antitumor immunity.

Keywords: Cancer immunotherapy; Germinal center B cell; Metabolic reprogramming; T follicular helper cell; Tertiary lymphoid structure.

Fig. 1

A schematic of factors and potential strategies for inducing tertiary lymphoid structure (TLS) through metabolism. Follicular helper T (Tfh) cell, germinal center (GC) B cell, innate lymphoid cell (ILC) and cytokine, high endothelial venule (HEV), and inflammatory signaling pathway may play a role in TLS formation. Alterations in glucose metabolism, lipid metabolism, amino acid metabolism, and vitamin metabolism may indirectly induce TLS formation in tumors by promoting the release, infiltration, or activation of these components

Fig. 2

Potential pathways to induce TLS through metabolic alterations. Abnormal expression of metabolism-related genes caused by metabolic disorders, and alterations in the levels of metabolites and enzymes favor the release of cytokine, the activation of the inflammatory signaling pathway, the activation and proliferation of lymphoid tissue inducer (LTi)/macrophage, the formation of HEV, and the differentiation and proliferation of Tfh cell and GC B cell. These metabolic changes may contribute to the formation of TLS via cytokine, inflammatory pathway, LTi/macrophage, HEV, Tfh cell, and GC B cell. Tfh, follicular helper T; Th17, T helper 17; LTi, lymphoid tissue inducer; ILC3, group 3 innate lymphoid cell; DC, dendritic cell; HEV, high endothelial venule

Fig. 3

Challenges and prospects in metabolic and microbial induction of TLS. Tfh cell differentiation, GC B cell activation, and cytokine release can influence TLS formation, but the mechanism by which they directly induce TLS formation is unknown. Some bacteria and viruses have been shown to induce TLS, yet the role of metabolism in this process remains unclear. In the future, significant challenges remain in studying the mechanisms of TLS formation, inducing TLS via microorganisms, and understanding the role of metabolism in TLS formation. Further research will be conducted on mechanisms, strategies, and microorganisms. Tfh, follicular helper T; GC, germinal center; DC, dendritic cell; HEV, high endothelial venule