Colorectal cancer remains among the most frequently diagnosed malignancies worldwide and is a major cause of cancer-related mortality. While early-stage disease can often be treated successfully, recurrence and metastatic spread continue to account for a large proportion of deaths. The liver is a particularly common site of metastasis because tumor cells draining from the intestine enter the portal circulation and can establish secondary lesions there. Although genetic alterations within cancer cells are central to progression, the study suggests that signals released by immune cells in the tumor microenvironment can create conditions that make colorectal cancer more aggressive.

The investigators first examined IL-1β levels in patient samples and publicly available molecular datasets. IL-1β was substantially more abundant in colorectal cancer tissues than in matched or adjacent normal tissues. Higher levels were associated with features of advanced disease, including larger tumors, deeper tissue invasion, lymph-node involvement, and more advanced TNM stage. Analyses of tissue and serum samples further indicated that IL-1β could have diagnostic and prognostic relevance. In a cohort of 94 paired colorectal cancer tissue samples, the protein was elevated in malignant tissue, while serum analyses involving 235 patients supported an association between circulating IL-1β and colorectal cancer.

The source of this cytokine was investigated using single-cell transcriptomic analysis, immunofluorescence, flow cytometry, polymerase chain reaction, and Western blotting. Across these approaches, monocytes emerged as the predominant IL-1β-producing population within the colorectal tumor microenvironment. Monocytes are circulating innate immune cells that can enter tumors and develop into tumor-associated macrophage-like populations or other inflammatory states. When stimulated by tissue damage, microbial products, or tumor-derived signals, they can release cytokines that influence cancer-cell survival, proliferation, and movement. The findings place monocytes at the center of an inflammatory communication system that appears to intensify malignant behavior.

The researchers then mapped how IL-1β affects colorectal cancer cells at the molecular level. Binding of IL-1β to its receptor activates intracellular signaling pathways that converge on nuclear factor kappa B, or NF-κB. A central component of this pathway is the transcription factor p65, also known as RELA. In the study, IL-1β increased p65 phosphorylation and promoted its movement from the cytoplasm into the nucleus, where transcription factors bind regulatory DNA sequences and alter gene expression. The team found that activated p65 directly increased transcription of KRT7, a gene encoding keratin 7, a structural intermediate-filament protein associated in several cancers with invasion and poor clinical outcomes.

Evidence that KRT7 is a direct target of p65 came from complementary genomic and transcriptional experiments. CUT&Tag analysis, which identifies the genomic locations occupied by specific DNA-binding proteins or chromatin-associated factors, detected p65 enrichment at the KRT7 promoter. Luciferase reporter assays provided additional support: when the promoter region was linked to a reporter gene, p65 activation increased reporter activity, whereas disrupting the relevant regulatory region weakened the response. These results connect an extracellular inflammatory signal to a specific transcriptional event, showing how IL-1β can reprogram the behavior of colorectal cancer cells rather than simply acting as a general growth stimulus.

The study further described how KRT7 communicates with the integrin-linked kinase pathway. KRT7 was found to interact with integrin subunit alpha 1, or ITGA1, a cell-surface adhesion receptor. This interaction activated integrin-linked kinase, known as ILK, which is involved in transmitting signals from the extracellular matrix into the cell. ILK activation was accompanied by molecular features of epithelial–mesenchymal transition: the cancer cells displayed increased N-cadherin and vimentin, reduced E-cadherin, and greater formation of invadopodia. Invadopodia are actin-rich protrusions that concentrate matrix-degrading enzymes, allowing cancer cells to penetrate surrounding tissue. In functional assays, these molecular changes were associated with enhanced migration and invasion.

Rather than ending with KRT7 and ILK, the signaling pathway appeared to close into a positive feedback loop. ILK increased phosphorylation of p65 at serine 536, a modification associated with enhanced NF-κB transcriptional activity and nuclear localization. This additional p65 activation sustained KRT7 expression, which in turn continued to support ITGA1-associated ILK signaling. Such feedback circuits are biologically important because they can convert a temporary inflammatory stimulus into a persistent cellular state. In this case, monocyte-derived IL-1β may initiate the process, while the p65–KRT7–ILK circuit maintains the invasive program even as tumor cells adapt to their surroundings.

The researchers tested whether interrupting this pathway could restrain tumor progression. Treatment with anakinra, an antagonist of the IL-1 receptor already used clinically to treat certain inflammatory disorders, reduced colorectal cancer cell proliferation, migration, invasion, and EMT-related changes in laboratory experiments. In patient-derived xenograft models and mouse models in which tumor cells were introduced through the spleen to evaluate liver colonization, blocking IL-1β signaling suppressed tumor growth and metastatic development. By contrast, adding exogenous IL-1β accelerated aggressive behavior in cultured cells and promoted tumor progression in animal experiments. These findings do not establish an immediate cancer treatment, but they provide a mechanistic rationale for investigating IL-1β pathway inhibitors, alone or alongside existing therapies, in carefully selected colorectal cancer patients.

The study identifies monocyte-secreted IL-1β as a potential bridge between inflammation and metastatic colorectal cancer. Its proposed p65–KRT7–ILK feedback circuit offers both biomarker and therapeutic possibilities, because elevated IL-1β or activation of downstream components may help identify tumors with a particularly invasive phenotype. However, further work will be needed to determine which patients would benefit from IL-1β blockade, how treatment might interact with chemotherapy or immunotherapy, and whether inhibiting this pathway can control established metastases without compromising protective immune functions. By tracing the pathway from immune-cell cytokine release to cancer-cell invasion, the findings strengthen the case that the tumor microenvironment is not merely a backdrop to cancer progression, but an active driver of disease.

Subject of Research: Monocyte-derived interleukin-1β and its role in colorectal cancer progression, epithelial–mesenchymal transition, tumor growth, and liver metastasis.

Article Title: Monocyte secretory IL-1β promotes colorectal cancer epithelial–mesenchymal transition via the p65–KRT7–ILK feedback

Web References: Genes & Diseases: https://www.sciencedirect.com/journal/genes-and-diseases ; DOI: https://doi.org/10.1016/j.gendis.2026.102250

References: Chen Z, He K, Peng D, Gao D, Zhang H, Liang X, Xu X, Du D, Wang L, Zeng L, Zeng Z, Wu X. “Monocyte secretory IL-1β promotes colorectal cancer epithelial–mesenchymal transition via the p65–KRT7–ILK feedback.” Genes & Diseases. DOI: 10.1016/j.gendis.2026.102250

Image Credits: Zhenzhou Chen, Kuan He, Dong Peng, Donghui Gao, Hongyu Zhang, Xiaolong Liang, Xiang Xu, Dongli Du, Luyue Wang, Li Zeng, Zongyue Zeng, Xingye Wu.

Keywords: Colorectal cancer, IL-1β, monocytes, tumor microenvironment, NF-κB, p65, KRT7, integrin-linked kinase, ILK, epithelial–mesenchymal transition, metastasis, liver metastasis, anakinra.

Matrix metalloproteinases (MMPs) have long been implicated in cancer biology, notable for their ability to degrade extracellular matrix components and thus facilitate tumor invasion and metastasis. The focus of this novel research centers on MMP1, a collagenase widely expressed in various malignancies but poorly understood in terms of its cellular heterogeneity and functional impact within tumor ecosystems. Utilizing single-cell RNA sequencing (scRNA-seq), the researchers parsed heterogeneous tumor populations, identifying a distinct subset of malignant cells characterized by high MMP1 expression. This subset exhibited unique transcriptional signatures suggestive of enhanced migratory capacity and immunomodulatory potential.

Spatial transcriptomics further enriched the analysis by mapping these MMP1+ malignant subsets within their native tissue architecture, revealing their preferential localization in tumor regions interfacing with immune infiltrates. This spatial context exposed dynamic interactions between MMP1+ tumor cells and various immune cell types, including cytotoxic T lymphocytes, regulatory T cells, and tumor-associated macrophages. Notably, the proximity of MMP1+ cells to immunosuppressive microenvironments implies a strategic positioning that may facilitate immune escape.

Functional assays corroborated the transcriptomic data, demonstrating that MMP1+ malignant cells secrete factors that modulate immune cell behavior. These secreted molecules appear to skew macrophages towards a tumor-promoting, M2-like phenotype while concurrently dampening T cell activation. Such immune reprogramming presents formidable challenges for immunotherapy, highlighting the necessity of targeting these specific tumor subsets for improved clinical outcomes.

Advanced computational modeling illuminated the signaling networks underpinning these interactions, identifying key pathways such as the TGF-β and NF-κB cascades as central mediators orchestrating this tumor-immune dialogue. The study suggests that MMP1 expression is not merely a marker but a functional driver of a pro-tumorigenic niche, potentially through direct remodeling of the extracellular matrix and indirect modulation of immune cell phenotypes.

Importantly, comparison across multiple cancer types revealed that the emergence of MMP1+ malignant subsets is a conserved feature associated with aggressive disease phenotypes and poor prognosis. This finding underscores the broad relevance of these subsets beyond a single tumor context, opening avenues for pan-cancer therapeutic strategies targeting the MMP1 axis.

The researchers also observed that therapeutic interventions, including chemotherapy and immune checkpoint blockade, inadvertently select for expansion of these MMP1+ subsets, potentially contributing to treatment resistance. This adaptive tumor evolution suggests an urgent need for combinatorial therapies that can neutralize the immunosuppressive activities of MMP1+ cells while preserving immune effector functions.

Delving deeper into the mechanistic underpinnings, the study explored how MMP1-mediated extracellular matrix remodeling influences immune cell infiltration and spatial distribution. Alterations in matrix stiffness and composition were shown to affect immune cell motility and localization, thus physically shaping the immune landscape within tumors. This mechanical remodeling likely synergizes with biochemical signals to establish an immunosuppressive milieu advantageous for tumor persistence.

The application of integrated single-cell and spatial ‘omics’ exemplifies the power of multidimensional profiling in unlocking tumor complexity. This approach transcends limitations of bulk analyses, capturing cellular heterogeneity and spatial heterogeneity simultaneously. The rich datasets generated serve as a valuable resource for the cancer research community, providing a roadmap for dissecting tumor ecosystems at unprecedented resolution.

From a translational perspective, targeting MMP1+ malignant subsets offers tantalizing therapeutic potential. Novel inhibitors specifically designed to disrupt MMP1 enzymatic activity or its downstream signaling nodes could arrest tumor progression and reinvigorate anti-tumor immunity. Moreover, the spatial co-localization of these subsets with immune cells suggests that spatially guided delivery of such agents may enhance efficacy and minimize off-target effects.

The implications of this study extend beyond oncology. The intricate tumor-immune communications mediated by MMP1+ cells may also hold relevance in fibrotic diseases and chronic inflammatory conditions where matrix remodeling and immune regulation intersect. Therefore, the identified pathways and cellular subsets might represent universal modulators of tissue homeostasis and pathology.

Future research will undoubtedly build upon these findings by investigating the plasticity of MMP1+ malignant subsets under varying microenvironmental conditions and treatment pressures. Understanding how these cells evolve and adapt could illuminate strategies to prevent or overcome therapeutic resistance. Furthermore, integrating proteomic and epigenomic data layers could deepen comprehension of the regulatory circuits governing MMP1 expression and function.

This landmark study reinforces the necessity of dissecting tumor heterogeneity in the context of spatial dynamics. By decoding the multifaceted roles of MMP1+ malignant subsets, the research paves the way for innovative diagnostic tools capable of stratifying patients based on the presence and activity of these cells. Such stratification could enable personalized interventions aimed at disrupting the deleterious tumor-immune interplay.

In summary, the work by Xu and colleagues constitutes a significant leap forward in cancer biology, elucidating how MMP1+ malignant cells engineer their microenvironment to thwart immune responses. Through meticulous single-cell and spatial transcriptomic analyses, the study highlights the importance of tumor cell heterogeneity and spatial context in shaping immune landscapes. This paradigm shift holds promise for developing next-generation therapies that more effectively harness the immune system against cancer.

As the oncology community digests these insights, one fact becomes clear: tumor progression is not solely a consequence of malignant transformation but also a product of dynamic, spatially orchestrated interactions between cancer cells and their immune counterparts. Targeting these cellular dialogues through innovative molecular interventions represents a bold frontier in the quest to conquer cancer.

Subject of Research: The role and impact of MMP1-positive malignant tumor cell subsets on tumor-immune interactions, elucidated through single-cell and spatial transcriptomic analyses.

Article Title: Decoding the impact of MMP1+ malignant subsets on tumor-immune interactions: insights from single-cell and spatial transcriptomics.

Article References: Xu, DM., Chen, LX., Xue, T. et al. Decoding the impact of MMP1+ malignant subsets on tumor-immune interactions: insights from single-cell and spatial transcriptomics. Cell Death Discov. 11, 244 (2025). https://doi.org/10.1038/s41420-025-02503-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02503-y