The research effort was led by Ilkyu Park, Jae-Ghi Lee, and Jisup Kim, who contributed equally to the work, under the corresponding authorship of Jung Ho Kim at Gachon University Gil Medical Center in Incheon. Rather than relying on bulk sequencing, which averages molecular signals across large chunks of tissue and destroys the crucial architectural context in which cells operate, the team embraced a dual-platform strategy. GeoMx Digital Spatial Profiling allowed them to measure gene expression across precisely annotated regions of interest, while CosMx Spatial Molecular Imaging delivered single-cell and subcellular resolution across hundreds of fields of view. Together, these technologies enabled the researchers to observe not merely which genes were active, but exactly where in the tissue those genes were being switched on and which neighboring cells were talking to one another.

The scale of the study is one of its distinguishing strengths. The investigators analyzed tissue from 89 colorectal cancer patients across 288 carefully annotated regions, encompassing tumor compartments, adjacent normal mucosa, stromal zones, and adipose tissue. They then validated and extended their observations in an independent cohort of 24 patients, evenly split between 12 individuals with obesity and 12 without, spanning 969 individual fields of view. This depth of sampling across both pre-neoplastic and tumor states allowed the team to trace molecular trajectories through time, comparing obese-normal mucosa, non-obese-normal mucosa, tumors from patients with obesity, and tumors from patients without obesity, using formalin-fixed paraffin-embedded clinical specimens that reflect real-world pathology practice.

The first major discovery emerged from an unexpected place: tissue that looked perfectly healthy under the microscope. In the normal-appearing mucosa of patients with obesity, the researchers identified a transcriptionally shifted epithelial state, meaning the genes expressed by the intestinal lining cells had already drifted into a different program even though the tissue retained its normal morphology. Within this obese-normal tissue, the team detected two distinct expression trajectories among a set of 30 genes linked to colorectal cancer. Crucially, a subset of these genes displayed early transcriptional alterations in the obese-normal tissue that were maintained all the way through tumor development. In other words, obesity appears to imprint a molecular signature on the gut epithelium before any visible lesion arises, and that signature persists as cancer takes hold, functioning as a kind of molecular breadcrumb trail from healthy tissue to malignancy.

This pre-neoplastic reprogramming carries significant implications for how scientists think about cancer initiation. The conventional view of carcinogenesis often centers on mutations accumulating over decades, but this work suggests that the systemic metabolic environment created by obesity can push epithelial cells into altered transcriptional states long before genetic damage is fully manifest in tissue architecture. Pathways related to epithelial identity and metabolic reprogramming, including signatures consistent with shifts in processes such as the pentose phosphate pathway and epithelial-mesenchymal transition programs, appear to be engaged in this early phase. If the epithelial lining of a person with obesity is already operating under a different gene-expression regime, interventions aimed at preventing colorectal cancer in this population may need to begin earlier and target these early transcriptional changes rather than waiting for polyps or tumors to appear.

The second phase of the obesity-driven reprogramming unfolds within the tumor itself, and it is immunological in nature. As tumors progressed in patients with obesity, the spatial organization of immune cells inside the tumor microenvironment changed in a distinctly unfavorable direction. The researchers documented a localized enrichment of macrophages expressing SPP1, a gene encoding the secreted protein osteopontin that has been implicated in tumor progression, metastasis, and immune evasion across multiple cancer types. These SPP1-positive macrophages were not scattered uniformly through the tissue; instead, they accumulated in specific spatial niches, clustering near cancer cells where their positioning could most effectively shape tumor behavior.

Even more telling was the ratio shift the team observed. In obese tumors, the balance between SPP1-positive macrophages and pro-inflammatory macrophages changed in favor of the SPP1-positive population, particularly in the regions immediately adjacent to cancer cells. At the same time, the spatial analysis revealed enhanced growth-factor and cytokine-mediated signaling emanating from these localized immune niches. This pattern describes a form of spatially restricted immunosuppression: rather than a wholesale depletion of immune cells, obesity appears to redistribute the immune landscape so that pro-tumor, tissue-remodeling macrophage states dominate the critical interfaces where tumors and immune defenses meet. Such remodeling could help explain clinical observations that obesity-associated colorectal cancers often behave more aggressively and respond differently to immunotherapy than tumors arising in patients of normal weight.

Synthesizing these observations, the authors propose a two-phase model of obesity-driven colorectal carcinogenesis. In the first phase, obesity induces early epithelial transcriptional reprogramming in morphologically intact mucosa, priming the tissue for transformation. In the second phase, once tumors have formed, obesity fosters spatially constrained immunosuppressive remodeling, concentrating SPP1-positive macrophages and pro-tumor signaling at the tumor-immune frontier. The two phases are complementary: an epithelium already nudged toward a cancer-prone transcriptional state faces a tumor microenvironment that has been simultaneously engineered to suppress the immune responses that might otherwise eliminate emerging malignant cells. This dual mechanism reframes obesity not simply as a statistical risk factor but as an active biological agent that rewrites both the target tissue and its defensive ecosystem.

The technical achievement underlying these conclusions deserves emphasis, because it illustrates why spatial transcriptomics has become one of the most transformative tools in modern cancer biology. Traditional single-cell RNA sequencing requires dissociating tissue, losing the spatial coordinates that define how cells actually interact in the body. The GeoMx and CosMx platforms used in this study preserved those coordinates, allowing the researchers to interrogate tumor cores, invasive margins, stromal compartments, adipose depots, and normal mucosa within the same specimens. The identification of cell-cell interaction networks, immune composition shifts, and expression trajectories would have been impossible with dissociative methods, and the concordance of findings across two independent platforms and two patient cohorts strengthens the reliability of the results considerably.

Clinically, the study opens several concrete avenues. The early epithelial gene-expression signature identified in obese-normal mucosa could serve as the basis for biomarker panels that stratify colorectal cancer risk in patients with obesity, potentially guiding the timing and intensity of colonoscopy surveillance. The spatially defined enrichment of SPP1-positive macrophages suggests a specific, targetable node in the immunosuppressive architecture of obesity-associated tumors; therapies designed to deplete, repolarize, or block the recruitment of this macrophage subset could restore anti-tumor immunity where it matters most. Moreover, because the macrophage remodeling is spatially restricted, combinatorial approaches that pair such targeted interventions with existing checkpoint inhibitor immunotherapies may prove particularly effective for this patient population. The work was supported by the National Research Foundation of Korea and approved by the institutional review board at Gachon University Gil Medical Center, with written informed consent obtained from all participants.

As obesity rates continue to climb worldwide and colorectal cancer incidence rises in younger populations, understanding the mechanistic links between the two has become a global health priority. This study demonstrates that the damage inflicted by obesity on colorectal tissue is not a late consequence of established disease but an early, detectable, and spatially organized process that unfolds across years of tumor evolution. By mapping that process at unprecedented resolution, the researchers have transformed obesity from a crude demographic risk marker into a set of actionable molecular and cellular targets, offering new hope that the elevated cancer burden carried by patients with obesity can one day be anticipated, intercepted, and treated with far greater precision than is possible today.

Subject of Research: Obesity-driven spatial reprogramming of the epithelial and immune ecosystem in colorectal cancer

Article Title: Obesity reprograms the spatial ecosystem of colorectal cancer through early epithelial reprogramming and immunosuppressive remodeling

Article References: Park, I., Lee, J.-G., Kim, J., Kim, S.-H., Nam, S., Lee, W.-S., Lee, H., Jang, Y., Chung, J.-W., Kim, K. O., Kwon, K. A., & Kim, J. H. (2026). Obesity reprograms the spatial ecosystem of colorectal cancer through early epithelial reprogramming and immunosuppressive remodeling. Genome Medicine. https://doi.org/10.1186/s13073-026-01758-z

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01758-z

Keywords: colorectal cancer, obesity, spatial transcriptomics, tumor microenvironment, epithelial reprogramming, SPP1 macrophages, immunosuppression, immune remodeling, cancer risk, Genome Medicine, immunotherapy, risk stratification