The LTB–LTBR–COL1A1 axis orchestrates a tolerogenic peritumoral tertiary lymphoid niche and enables multimodal prediction of metastasis in clear cell renal cell carcinoma

The TLS chemokine CXCL13 marked the TCN, correlated with immunosuppressive checkpoints, and behaved as a risk factor. In TCGA-KIRC, a TCN-positive/IMN-negative signature—concordant between ssGSEA and NNLS deconvolution—stratified markedly worse overall survival (log-rank P < 0.0001) and higher metastasis frequency (Fisher P < 0.001). Finally, a weakly-supervised histopathology model (CLAM) predicted metastasis from primary-tumor whole-slide images (mean out-of-fold AUC ≈ 0.78); a systematic fusion search adding niche/axis-gene panels yielded only marginal, non-significant gains over histology alone—confirmed by repeated cross-validation and bootstrapping—indicating that routine histology captures most of the metastasis-predictive signal while the niche genes supply concordant, interpretable risk that resolves discordant cases.

Multiplex immunofluorescence is planned to corroborate the spatial co-localization of the axis [Fig. 5, pending]. These data define an LTB–LTBR–COL1A1–driven tolerogenic peritumoral niche as a determinant of ccRCC metastasis and provide a deployable, image-anchored risk model.