Beyond TLS Presence: A Functional Framework Integrating Maturity, Location, and Immune Context

TLSs are ectopic, non-encapsulated aggregates of immune cells that develop de novo in non-lymphoid tissues in response to persistent antigenic stimulation and have emerged as clinically relevant features of many solid tumours. However, conventional TLS assessment based on presence/absence, density, or simplified maturation scales does not adequately explain why TLSs are associated with favourable, neutral, or even adverse clinical outcomes across tumour types and treatment settings. In this review, we synthesise the current biological, spatial, and clinical evidence and argue that TLSs should be interpreted not as static histologic findings but as functional immune niches shaped by three interacting axes: structural maturity, spatial localisation, and the functional immune context. We discuss how mature germinal centre-positive TLSs often reflect coordinated B-cell-T-cell cooperation and sustained antigen-driven anti-tumour immunity, whereas partially organised or suppressive TLSs may display transitional or immunoregulatory properties. On this basis, we propose a pragmatic, pathology-oriented conceptual framework that groups TLSs into three simplified functional states: TLS-A, representing mature effector TLSs with germinal centre activity; TLS-B, representing organised but incompletely matured or functionally intermediate TLSs; and TLS-C, representing TLSs dominated by regulatory or suppressive immune programs. We further place these states within recurrent tumour microenvironment archetypes and outline the rationale for a "proposed functional TLS score" integrating histopathologic and molecular readouts. Rather than introducing a definitive biological taxonomy, this framework is intended as a translational model for harmonising TLS interpretation, refining biomarker development, and supporting future studies on prognosis, immunotherapy response, and standardised pathology reporting in solid tumours. Because this framework is derived from a narrative synthesis of published evidence rather than from formal validation, it should be regarded as hypothesis-generating and requires prospective, tumour-specific validation before clinical implementation.