The role of tertiary lymphoid structures in renal cell carcinoma: From predictive biomarker to therapeutic target

In the evolving landscape of cancer immunotherapy, tertiary lymphoid structures (TLS) have rapidly transitioned from a histological curiosity to a central mediator of anti-tumour immunity. A growing body of evidence, particularly within renal cell carcinoma (RCC), has established a strong association between the presence of dense, mature TLS in the tumour microenvironment and significant clinical benefit from immune checkpoint inhibitor (ICI) therapy. The significance of TLS lies in their function as fully equipped, in situ immune factories where B cell maturation and antibody production occur, providing a compelling explanation for ’exceptional responders’ to immunotherapy. However, the clinical utility of TLS is rooted in its heterogeneity; intratumoral and mature TLS are most strongly associated with favourable outcomes. This letter discusses the dual role of TLS as a powerful predictive biomarker for ICI efficacy in RCC and as an actionable therapeutic target. It highlights the current understanding and paves the way for future strategies focused on standardizing TLS assessment and developing innovative therapies to induce mature TLS, aiming to convert immunologically ‘cold’ tumours into ‘hot’ ones.