Glucose-Hungry Macrophages Block Cancer-Killing T Cells in Lung Tumors

Despite the revolutionary impact of immune checkpoint blockade (ICB) on lung cancer treatment, the majority of NSCLC patients do not achieve durable responses, and predictive biomarkers remain inadequate. This study addresses a critical gap: how macrophage glucose metabolism sculpts the spatial architecture of the tumor immune microenvironment to suppress CD8+ T cell activity and drive resistance to anti-PD-(L)1 therapy.

Using spatial transcriptomics from three in-house NSCLC surgical specimens, the authors screened all 14 SLC2A family glucose transporters for correlations with IFN-γ-related and ICB-responsive gene signatures. SLC2A1 emerged as the most negatively correlated transporter, a finding validated in TCGA and GEO bulk RNA-seq datasets. Local indicators of spatial association (LISA) and bivariate Moran's I analysis in 38 clinical NSCLC samples confirmed that SLC2A1 expression was inversely associated with CD8+ T cell density across tumor tissue. Critically, this negative spatial relationship was reproduced in both subcutaneous LLC allograft and orthotopic lung cancer mouse models.

Cell-type deconvolution and single-cell analyses pinpointed TAMs—not tumor cells—as the primary source of SLC2A1 in NSCLC. TAM-specific conditional knockout of Slc2a1 (using LysM-Cre mice) significantly suppressed tumor growth and enhanced both the spatial homogeneity and effector function of intratumoral CD8+ T cells, including increased IFN-γ and granzyme B production. Tumor cell-specific Slc2a1 knockdown failed to replicate these effects. Pharmacological inhibition of SLC2A1 phenocopied the macrophage-specific genetic deletion and synergized with αPD-L1 therapy to further reduce tumor burden. Mechanistically, SLC2A1+ TAMs appeared to outcompete CD8+ T cells for glucose, limiting glycolytic capacity and IFN-γ production in T cells while sustaining their own immunosuppressive program.

Spatial profiling of human NSCLC specimens revealed that regions enriched in SLC2A1+ TAMs harbored significantly lower CD8+ T cell densities. Importantly, shorter spatial distances between SLC2A1+ TAMs and CD8+ T cells correlated with resistance to αPD-(L)1 therapies, establishing this spatial proximity metric as a potential clinical biomarker.

These findings reframe TAM immunosuppression as a spatially organized, metabolically driven process and identify TAM-specific SLC2A1 as a tractable therapeutic target. Combining SLC2A1 inhibition with checkpoint blockade represents a promising strategy to convert immunologically cold tumors into responsive ones.