The results identify associations rather than establish that metabolism directly causes T-cell exclusion, and the authors emphasize that the spatial analysis included only 12 patients, with particularly few usable immune-cell regions in the low-infiltration group. Previous work in this series of patients had linked denser pretreatment infiltration of CD8-positive T cells to a complete pathological response after neoadjuvant chemoradiotherapy. In the new analysis, four of six tumors with the highest CD8 scores showed a complete response, whereas none of the six with the lowest scores did.

That association prompted the team to search for cancer-cell-intrinsic and immune-cell features that differed between inflamed and excluded regions. Using the GeoMx Digital Spatial Profiler, the researchers profiled the whole transcriptome in treatment-naive, stage II or III esophageal or gastroesophageal-junction adenocarcinomas. A pathologist selected regions of interest, after which cancer cells identified by cytokeratin staining and immune cells identified by CD45 staining were analyzed separately.

After quality control, 34 cancer-cell segments and 22 immune-cell segments remained for further study, drawn from 41 regions across the 12 selected tumors. The selected patients represented the extremes of CD8 infiltration: the final set had a median of 20.6 CD8-positive cells per square millimeter in the low group and 224.2 per square millimeter in the high group. Cancer-cell profiles separated mainly according to the tumor’s CD8-infiltration status.

Regions from the same patient generally clustered together, suggesting that patient-specific programs were important, although one tumor contained both CD8-low and CD8-high transcriptional regions. These cancer cells expressed higher levels of APOA1 and APOA4, lipid transporters associated with cholesterol handling; PPARGC1A, which regulates mitochondrial biogenesis and oxidative metabolism; and OXCT1, a mitochondrial enzyme involved in ketone-body metabolism. Such metabolic differences were more prominent than differences in canonical oncogenic pathways.

Pathway analysis reinforced the metabolic pattern. Of 400 differentially expressed pathways, lipid-related programs—including high-density lipoprotein and chylomicron remodeling, lipoprotein remodeling and ketone metabolism—were elevated in cancer cells from CD8-low tumors. In contrast, CD8-high regions showed stronger antigen-presentation, interferon-alpha signaling, interleukin-7 signaling and Fas-mediated immune-apoptosis pathways.

The low-infiltration cancer cells also displayed several immune-suppressive features: reduced expression of antigen-presentation components in half of the affected patients, increased checkpoint-related transcripts, and higher expression of the tryptophan-depleting enzyme IDO1. At the same time, they expressed cancer-testis antigens that can elicit T-cell responses, underscoring the possibility that tumor cells may suppress presentation of antigens capable of attracting an immune response. The immune-cell compartments pointed in a similar direction, although the evidence was less balanced.

Only four CD45-positive segments from three CD8-low tumors passed quality control, compared with 18 segments from five CD8-high tumors, because immune-cell-depleted regions often yielded too few CD45-positive cells. In the available low-infiltration material, APOA1, APOA4, LGALS2, MMP1 and INHBA were enriched; these genes are associated with lipid metabolism or suppressive myeloid-cell populations. Single-sample pathway analysis also identified steroid-hormone metabolism, amino-acid and peptide transport, ubiquinol biosynthesis and the PGC-1alpha program in the low-infiltration immune compartments.

PGC-1alpha is a central regulator of mitochondrial biogenesis, making its enrichment compatible with a population of myeloid cells that depends more on oxidative phosphorylation than glycolysis. The researchers then tested whether the association appeared in a larger, independent dataset. They analyzed bulk messenger-RNA profiles from 65 treatment-naive, chromosomally unstable esophageal adenocarcinomas in The Cancer Genome Atlas and divided patients by the median cytotoxic T-lymphocyte signature.

Tumors in the lower half ranked highly for mitochondrial translation, respiratory electron transport, the tricarboxylic acid cycle and oxidative phosphorylation. Single-sample analysis also associated cholesterol metabolism with greater macrophage infiltration and ketone-body metabolism with lower CD8-positive T-cell infiltration. These results support a broad association between mitochondrial metabolic programs and lymphocyte-poor tumors, but the retrospective bulk data cannot show that the pathways caused the difference in immune composition.

Fresh tissue provided a functional test of the transcriptomic observations. Using SCENITH, a flow-cytometry assay that estimates dependence on glycolysis or mitochondrial oxidative phosphorylation from changes in protein synthesis, the team profiled five resected tumors, including esophageal, gastroesophageal-junction and gastric adenocarcinomas. Three specimens were dominated by macrophages and classified as T-cell-low, whereas two lymphocyte-rich tumors included a microsatellite-instable cancer used as a positive control.

Macrophage-like cells from the T-cell-low cancers showed greater mitochondrial dependence, while those from lymphocyte-rich tumors were more glycolysis-dominant. Because the five specimens differed in anatomical origin, prior treatment and immune composition, the experiment supports the proposed metabolic association but does not isolate tumor biology from specimen-level differences. Separate co-culture experiments offered a possible mechanism.

Cancer cell lines with greater oxidative-phosphorylation reliance tended to produce a lower ratio of the macrophage marker CD80 to the alternative-activation marker CD163 than lines relying more on glycolysis, suggesting a shift toward a less inflammatory macrophage phenotype. The result varied among monocyte donors, and the most glycolytic line did not increase the CD80-to-CD163 ratio, indicating that cytokines, direct cell contact and other factors also shape macrophage state. The experiment therefore supports an association between tumor-cell metabolism and macrophage polarization rather than proving that OXPHOS alone causes suppression.

The authors noted that lipid-rich environments can favor mitochondrial respiration in regulatory and myeloid cells, while providing less favorable metabolic conditions for antitumor T cells. Together, the findings nominate lipid metabolism and mitochondrial respiration as possible contributors to the T-cell-excluded state in esophageal adenocarcinoma, while also highlighting reduced antigen presentation as a complementary mechanism. They provide a rationale for testing metabolic interventions alongside immune activation, but they do not demonstrate that such treatment will improve outcomes in patients.

The study was limited by its small selected cohort, unequal immune-segment numbers, retrospective validation dataset and heterogeneous ex vivo samples. The authors have initiated a clinical trial using metformin as a metabolic modulator to test more directly whether changing metabolism can modify the antitumor immune response. Until controlled clinical results are available, the central conclusion is that oxygen-consuming, lipid-linked metabolic states mark esophageal adenocarcinomas that exclude CD8-positive T cells and may help explain resistance to existing immune-directed therapy.

Subject of Research: Spatial analysis of metabolic programs associated with T-cell exclusion in esophageal adenocarcinoma

Article Title: Spatial transcriptomic sequencing identifies lipid metabolism and mitochondrial respiration as central features of T cell excluded esophageal adenocarcinomas

Article References: Sanders, J., Hahn, N., Bos, E. N., van Schie, D. M., Nijman, I. J., van Grieken, N. C. T., van der Peet, D. L., van Laarhoven, H. W. M., Grootjans, J., Bijlsma, M. F., Van den Bossche, J., de Gruijl, T. D., & Derks, S. (2026). Spatial transcriptomic sequencing identifies lipid metabolism and mitochondrial respiration as central features of T cell excluded esophageal adenocarcinomas. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03635-3

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03635-3

Keywords: esophageal adenocarcinoma, spatial transcriptomics, T-cell exclusion, lipid metabolism, mitochondrial respiration, oxidative phosphorylation, tumor microenvironment, macrophages, antigen presentation, immune suppression, Spatial, transcriptomic

SPP1 is a secreted glycosylated phosphoprotein with a long-established resume in skeletal biology, where it participates in bone mineralization and the remodeling of the extracellular matrix. But in tumors, the same molecule takes on a darker role. The review synthesizes evidence showing that SPP1 is produced by multiple players within the tumor microenvironment, including tumor cells themselves, tumor-associated macrophages and cancer-associated fibroblasts. Once secreted, it signals through a family of cell-surface receptors, chiefly integrins that recognize its arginine-glycine-aspartic acid motif, as well as variants of the CD44 receptor. Through these interactions, SPP1 transmits instructions that reshape how immune cells behave, how they move through tissue, and whether they can reach the tumor at all.

One of the most consequential effects of SPP1 signaling is its influence on macrophages, the versatile immune cells that populate nearly every tumor. The review describes how SPP1 drives the polarization of tumor-associated macrophages toward a pro-tumor phenotype, a state in which these cells abandon their immune-surveillance duties and instead support tumor growth, angiogenesis and tissue remodeling. Single-cell RNA sequencing studies, which allow researchers to profile gene expression in individual cells, have repeatedly identified distinct populations of SPP1-positive macrophages in human tumors, and these cells are consistently associated with poor clinical outcomes. Rather than simply being bystanders, these macrophages appear to be active architects of an immunosuppressive environment, secreting SPP1 that reinforces their own suppressive identity and that of their neighbors.

The consequences extend well beyond macrophages. According to the review, SPP1 impairs the function of innate immune cells, the rapid-response arm of the immune system that includes natural killer cells and dendritic cells. It also induces the exclusion and exhaustion of T cells, the cytotoxic lymphocytes that immunotherapies such as immune checkpoint inhibitors are designed to unleash. T cell exhaustion is a state of progressive dysfunction in which T cells lose their ability to kill tumor cells, and SPP1 appears to promote this process while simultaneously building physical barriers that keep T cells away from tumor cells in the first place. By remodeling the extracellular matrix, the fibrous scaffold that permeates tumors, SPP1 helps create a form of immune exclusion in which anti-tumor lymphocytes linger at the tumor margin, unable to penetrate the tumor core.

This combination of effects helps explain why many patients fail to respond to immune checkpoint inhibitors, the blockbuster therapies that block inhibitory receptors such as PD-1 and have transformed the treatment of melanoma, lung cancer and other malignancies. Checkpoint inhibitors work best in tumors that are already infiltrated by T cells, so-called hot tumors. SPP1-rich tumors, by contrast, tend to be cold, lacking meaningful lymphocyte infiltration and exhibiting dense, suppressive stroma. The review positions the SPP1 axis as a promising therapeutic target precisely because it operates upstream of these failures: neutralizing SPP1 or blocking its receptors could convert a cold, excluded tumor into one that immune therapies can actually reach.

Encouragingly, the review catalogs a growing arsenal of strategies aimed at doing exactly that. Direct SPP1 neutralization, using antibodies or other decoy molecules, aims to mop up the protein before it reaches its receptors. Receptor blockade seeks to sever the downstream signaling that integrins and CD44 variants transmit into immune and stromal cells. A third approach targets the source: depleting or reprogramming the SPP1-positive tumor-associated macrophages that manufacture much of the tumor’s supply. Each strategy attacks a different node of the axis, and the review suggests that combining them with existing modalities may be where the greatest potential lies.

Those combination possibilities are particularly striking. The authors describe evidence supporting the pairing of SPP1 targeting with immune checkpoint inhibitors, with agonists of the STING pathway, a innate immune sensor that when activated can ignite anti-tumor inflammation, with cytokine-based therapies, and with conventional treatments such as radiotherapy and chemotherapy. The logic is complementary: SPP1 blockade dismantles the immunosuppressive and exclusionary architecture of the tumor, while the partner therapy supplies or amplifies the immune attack. Radiotherapy and chemotherapy, for their part, can release tumor antigens and induce immunogenic cell death, effects that SPP1 targeting may help convert into durable systemic immunity rather than transient local responses.

Drug delivery innovation is also entering the picture. The review highlights work on lipid nanoparticles, the same lipid-based vehicles that proved their worth in mRNA vaccines, engineered to deliver SPP1-targeting small interfering RNA into tumors. One described design uses mannosylated nanoparticles, decorated with sugar molecules that guide them toward macrophages, to deliver SPP1 siRNA in combination with interferon-gamma, a cytokine that can push macrophages back toward an anti-tumor state. Such approaches illustrate how the field is moving beyond simple antibody blockade toward precision tools that can reprogram specific cell populations within the tumor microenvironment, potentially resetting the balance between suppression and immunity at its source.

Yet the review is careful to temper enthusiasm with a sober accounting of the translational challenges ahead. SPP1 signaling is context-dependent: the same molecule can exert different, sometimes opposing, effects depending on the receptor engaged, the cell type targeted and the stage of tumor progression. Osteopontin has documented roles in normal wound healing and tissue homeostasis, raising the possibility that systemic blockade could interfere with beneficial biology. The authors also emphasize the need for biomarker development and patient stratification, since identifying which patients harbor SPP1-driven, immune-excluded tumors will be essential for selecting who benefits from SPP1-directed therapies and for designing clinical trials capable of demonstrating meaningful benefit.

The broader message of the review is that the tumor microenvironment is not a passive backdrop but an actively engineered landscape, and SPP1 is one of its chief engineers. By promoting pro-tumor macrophage polarization, disabling innate immunity, exhausting and excluding T cells, and hardening the extracellular matrix into a physical barrier, SPP1 sits at a convergence point of nearly every mechanism tumors use to hide from the immune system. The authors conclude that targeting the SPP1 axis offers a promising strategy for remodeling the tumor microenvironment and enhancing antitumor immunity, a conclusion that is likely to accelerate preclinical and clinical efforts. If those efforts succeed, a molecule named for its abundance in bone may become one of the most important levers for turning immunologically cold tumors into ones that modern immunotherapy can finally heat up.

Subject of Research: The role of secreted phosphoprotein 1 (SPP1) in regulating immunosuppression in the tumor microenvironment and therapeutic strategies targeting the SPP1 axis

Article Title: Reprogramming the tumor immune landscape through SPP1 targeting

Article References: Gao, L., Yang, J., & Teng, Y. (2026). Reprogramming the tumor immune landscape through SPP1 targeting. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03844-x

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03844-x

Keywords: SPP1, osteopontin, tumor microenvironment, tumor-associated macrophages, cancer-associated fibroblasts, immune evasion, T cell exclusion, immune checkpoint inhibitors, CD44, integrins, lipid nanoparticles, cancer immunotherapy