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.¹ 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 (TME) and significant clinical benefit from immune checkpoint inhibitor (ICI) therapy. A recent meta-analysis provided high-level evidence for this, confirming that high TLS density correlates with superior objective response rates and prolonged progression-free survival across solid tumours, including RCC.² This consensus is not only reshaping our understanding of the TME but also charting new paths for therapeutic innovation.

The significance of TLS lies in their function as fully equipped, in situ immune factories. Groundbreaking work using spatial transcriptomics has beautifully elucidated that within the TLS of RCC, a complete B cell maturation process occurs — from B cell recruitment and germinal centre reactions to the generation of antibody-producing plasma cells.³ These locally produced IgG antibodies can directly bind to and mark tumour cells for apoptosis. This elegant mechanism provides a compelling explanation for why TLS signatures are a key immunogenomic determinant for ‘exceptional responders’ to combination immunotherapy in RCC.⁴

However, the clinical utility of TLS is not a simple binary question; its value is deeply rooted in its heterogeneity. First, location and maturity are paramount. Studies indicate that it is the intratumoral and mature (i.e. secondary follicle-like) TLS that are most strongly associated with favourable outcomes and ICI efficacy.⁵ Second, the value of TLS is highly context-dependent on the surrounding immune milieu. A pivotal study proposed a more refined paradigm: optimal response to PD-1 blockade in RCC requires the combination of high TLS density with a low abundance of tissue-resident exhausted CD8⁺ T cells.⁶ This suggests that even a potent ‘immune factory’ is of limited use if the effector T cells are already terminally dysfunctional. This complex interplay may explain paradoxical reports of TLS correlating with poor prognosis in some RCC cohorts.⁷

These deepening insights are paving the way for clinical translation and future therapeutic strategies. To overcome the challenges of invasive biopsies, developing non-invasive surrogates is critical. An important clinical study has linked the baseline level of circulating unswitched memory B cells with the presence of intratumoral TLS and improved survival in patients with RCC treated with nivolumab, presenting a promising avenue for a liquid biopsy approach.⁸ This principle is not unique to RCC; similar efforts in other cancers have also successfully identified circulating T cell signatures that correlate with intratumoral TLS, reinforcing the feasibility of this approach.⁹ Furthermore, in the highly aggressive yet paradoxically ICI-sensitive sarcomatoid RCC subtype, TLS are now understood to be ‘pervasive’, providing a key mechanistic explanation for its unique immune sensitivity.¹⁰

Looking ahead, the field is poised to shift from passive prediction to active modulation. The ultimate goal is to therapeutically induce the formation and maturation of TLS, thereby converting immunologically ‘cold’ tumours into ‘hot’ ones. Excitingly, forward-looking research in bioengineering has already demonstrated the potential to generate functional TLS-like organoids in vitro that, when transplanted, can recruit immune cells and exert anti-tumour effects in vivo.¹¹

In conclusion, TLS represent not only a powerful predictive biomarker in RCC but also an actionable therapeutic target. First, future efforts must focus on standardizing TLS assessment and validating reliable circulating biomarkers. Furthermore, it is crucial to elucidate the key molecular pathways that govern TLS formation and maturation. Ultimately, this knowledge should guide the development of innovative therapies that can safely and effectively induce mature TLS in situ. By pursuing these avenues, we can translate our biological understanding of TLS into tangible clinical strategies that will profoundly improve outcomes for patients with RCC.

Chongxiang Gao and Du Cai drafted the initial version of the manuscript. Jianguang Qiu and Feng Gao reviewed the manuscript. All authors approved and agreed to publish the final version of the manuscript.

Not applicable.