Tertiary lymphoid structures and tumor-draining lymph nodes during checkpoint blockade: tracing clonal provenance, replenishment, and local maintenance

Tertiary lymphoid structures (TLSs) contribute to local antitumor immunity and are associated with favorable outcomes following immune checkpoint blockade (ICB). Studies of tumor-draining lymph nodes (TDLNs) identify continuing cellular supply, while stage-resolved experiments distinguish TLS formation from subsequent local maintenance. These advances leave a common attribution problem: the origin of responding clones, their continuing supply, and the site supporting their function are often examined separately. This review integrates clonal tracking, spatial profiling, antigen-specific assays, and timed perturbations to relate these processes across TDLNs, blood, TLSs, and tumor tissue. Building on experimental evidence for stage-dependent TLS maintenance, we distinguish cellular replenishment from local support and from distal antibody-mediated effects. Nodal precursor-like T cells generate tumor-infiltrating progeny in experimental models; human TLS studies identify reactive clones and local interactions that can support proliferation and differentiation. Differences in treatment exposure, TLS maturity, the populations perturbed, and measured outcomes help explain why these findings do not imply a uniform transition to nodal independence. We define the observations needed to distinguish local persistence, functional activity, and conditional autonomy during a specified restriction of external input. This framework links apparently divergent findings to testable predictions about when incoming cells or local support limit treatment responses, while keeping proposed mechanisms distinct from demonstrated effects.