Spatial Treg niches and the therapeutic reprogramming of tumour tolerance in cancer

Abstract

Regulatory T cells (Tregs) maintain immune homeostasis, but in cancer the same FOXP3-dependent programme can be co-opted to protect malignant tissue from immune elimination. This review critically synthesizes spatially resolved, single-cell and mechanistic evidence to determine when tumour-associated Tregs constitute active components of suppressive multicellular niches rather than merely correlates of immune exclusion. We integrate tumour-adapted regulatory states with anatomical positioning, neighbouring malignant and non-malignant cells, candidate suppressive mechanisms and upstream tumour-intrinsic, stromal and myeloid programmes. This framework distinguishes Treg-dominant suppressive niches from Treg-associated architectures in which regulatory-cell accumulation is secondary to other resistance mechanisms. We examine tumour nests, invasive margins, dendritic-cell and lymphoid aggregates, stromal and perivascular barriers, and hypoxic or metabolically constrained regions, assessing the strength of evidence linking each context to local immune restraint. We further consider how these niches emerge during tumour progression, change under therapeutic pressure, and persist, relocate or re-form during resistance. We evaluate selective depletion strategies targeting CCR8, CD25 and CTLA-4, together with functional reprogramming of TGF-β, adenosine, kynurenine, lactate, hypoxia and IL-2 pathways. Finally, we propose a tiered biomarker framework integrating Treg phenotype, transcriptional state, spatiotemporal topology, functional immune competence and longitudinal pharmacodynamic validation. The contribution of this Review is therefore not the niche concept itself, but its Treg-centred mechanistic and translational operationalization for identifying tumour-specific regulatory dependencies while preserving systemic self-tolerance.