Immune-excluded tumors are characterized by abundant CD8+ T cells at the invasive margin but scarce infiltration within tumor nests, leading to limited responses to immunotherapy. Emerging evidence identifies cancer-associated fibroblasts (CAFs) as key mediators of immune exclusion. This review highlights a glycolysis-driven CAFs (glyCAFs) pathway that orchestrates immune exclusion. Glycolysis CAFs upregulate Glucose Transporter 1 (GLUT1) to sustain CXCL16 secretion, which in turn engages CXCR6 on CD8+ T cells and effectively traps them at the tumor margin. We summarize the evidence supporting this glyCAF–GLUT1–CXCL16–CXCR6 signaling circuit and its functional impact on T-cell positioning. A distinct advantage of this axis lies in its ability to integrate a targetable metabolic phenotype with a spatially measurable immunologic outcome. We discuss potential spatial biomarkers—such as glyCAFs enrichment at the margin, elevated GLUT1 and CXCL16 expression, and CXCL16-high stromal niches closely associated with CD8+ T cells—and outline therapeutic strategies aimed at modulating this pathway. Pharmacologic inhibition of GLUT1 (e.g. BAY-876) can suppress glycolysis and CXCL16 production, while blockade of CXCL16 or CXCR6 may release T-cell retention and enhance responses to chemotherapy, radiotherapy, and immune-checkpoint blockade. Finally, we highlight open questions, regarding the cellular origins and regulatory networks of glyCAFs, the classification of the glyCAFs state as a transient adaptation or a stable entity and its biomarker potential, the spatial mechanisms of glyCAF–immune interplay through integrated metabolic and proteomic mapping, the preclinical validation of multi-target strategies informed by spatial biomarkers, and the preclinical validation of combinatorial therapeutic strategies using biomarker-guided approaches. The glyCAF–GLUT1–CXCL16–CXCR6 axis establishes a clear mechanistic and translational framework linking stromal metabolism to immune spatial architecture, paving the way for precision immunometabolic strategies to overcome T-cell exclusion in solid tumors.
Liu et al. (Mon,) studied this question.