It is demonstrated that the non-cellular tumor microenvironment preserved in PDSs is sufficient to drive coordinated transcriptional programs in both macrophages and cancer cells, and to guide future strategies targeting macrophage-cancer cell crosstalk in breast cancer.
Abstract
Breast cancer progression is critically shaped by the tumor microenvironment, yet models that preserve patient-specific microenvironmental complexity remain limited. In particular, how the non-cellular microenvironment regulates macrophage-cancer cell crosstalk and contributes to tumor aggressiveness remains poorly understood. Here, we establish a patient-derived scaffold (PDS) model derived from decellularized breast cancer tissues as a platform to interrogate these interactions. Growth of MDA-MB-231 and MCF-7 cancer cells in PDSs reshaped cytokine gene expression and secretory profiles, leading to transcriptional reprogramming of THP-1 monocytes. Additionally, THP-1 cells were able to infiltrate PDSs and adopted macrophage-like states characterized by increased expression of M2- and pluripotency-related genes, alongside reduced proliferation signatures. Strikingly, transcriptional analysis of THP-1 PDS cultures identified a subset of PDSs derived from estrogen receptor-negative, CD163high tumors that preferentially induced upregulation of gene programs associated with macrophage differentiation and immunoregulatory gene signatures. Secreted molecules from these THP-1 PDS cultures, in turn, enhanced epithelial-to-mesenchymal transition (EMT)-related and immune-associated gene expression in cancer cells, particularly in MDA-MB-231, revealing transcriptional crosstalk linked to aggressive tumor features. Together, our findings demonstrate that the non-cellular tumor microenvironment preserved in PDSs is sufficient to drive coordinated transcriptional programs in both macrophages and cancer cells. The strong concordance between PDS-induced responses and clinical tumor characteristics underscores the potential of PDS-based models to uncover patient-specific tumor microenvironment interactions and guide future strategies targeting macrophage-cancer cell crosstalk in breast cancer.
Integrative single-cell RNA sequencing analysis of publicly available datasets from non-small cell lung cancer and breast cancer is performed to systematically map transcriptional heterogeneity and regulatory networks within the TME, providing a systems-level framework of TME organization.
M. O. Odubote, Chiemeka Elochi Emeribe· bioRxiv· 0 citations
Cancer cells acquire malignant traits through epigenetic remodeling driven by inflammatory secretomes in the tumor microenvironment. However, how immune-derived inflammatory factors regulate cancer cell epigenetics remains poorly understood. Here, we show that IL-26 produced by tumor-specific type 17 T cells acts as a key mediator of epigenetic reprogramming associated with cancer malignancy. We identify selective accumulation of IL-26–expressing T cells in colorectal tumors resistant to immune checkpoint blockade therapy. IL-26 functions as a noncanonical cytokine by translocating into the nucleus of tumor cells, where it directly binds STAT1 and forms transcriptional complexes with NF-κB and AP-1. Nuclear IL-26 induces a transcriptionally active chromatin state characterized by BRD4 and H3K27ac enrichment, resulting in upregulation of CXCL chemokines. This process promotes neutrophil infiltration and enhances immune evasion and tumor progression by suppressing CD8 + T cell responses. Together, these findings support a model in which tumor-specific type 17 T cells directly reprogram cancer cell epigenetics through IL-26, reshaping the tumor immune microenvironment to promote immune evasion. How immune-derived inflammatory factors shape cancer cell epigenetics to promote immune checkpoint blockade resistance remains to be explored. The authors here show that IL-26 from type 17 T cells induces BRD4-dependent epigenetic remodeling in cancer-cell nuclei, thereby promoting malignant progression and immune evasion.
T. Itoh, R. Hatano, Y. Hasegawa et al.· Nature Communications· 0 citations
The tumor microenvironment (TME) critically regulates cancer progression by providing biochemical and biophysical cues that shape cellular behavior. However, how defined physical microenvironments govern cancer stemness and chemoresistance through mechanotransduction remains poorly understood. Here, we systematically engineered eight tumor-mimetic microenvironments by integrating serum, oxygen, and 3D compacted culture to investigate their effects on A549 non-small cell lung cancer cells. Among all conditions, cells cultured under 3D culture (PM4C) exhibited reduced cellular stiffness, enhanced expression of cancer stemness markers (EpCAM and CD44), and significantly increased resistance to cisplatin in both in vitro and nude mouse xenograft models. Transcriptomic analysis revealed that differentially expressed genes in the PM4C group were predominantly enriched in cell adhesion, mechanotransduction, stemness, and cisplatin resistance pathways. Metabolomic profiling further revealed a substantial accumulation of anaerobic metabolites associated with the maintenance of stemness. Mechanistically, the PM4C microenvironment remodeled matrix production, cell-ECM interactions, and cytoskeletal organization while inducing epigenetic reprogramming (reduced H3K9 acetylation), collectively promoting a stem-like and chemoresistant phenotype. These findings establish a direct mechanistic link between TME and cancer cell stemness, demonstrating that TME can reprogram stemness and drug responsiveness through mechano-epigenetic regulation. This work provides a mechanobiological framework for engineering physiologically relevant tumor organoids and offers new strategies for developing TME-targeted drugs and therapies.
Duoduo Zhang, Yung-Chiang Liu, Chunchang Li et al.· ACS Applied Materials and In...· 0 citations
Introduction Colorectal cancer (CRC) is a heterogeneous malignancy and a major cause of cancer-related mortality worldwide. Cancer-associated fibroblasts (CAFs) accumulate in tumors and correlate with poor patient survival, suggesting a central role in immune regulation. Patient-derived organoids (PDO) maintain the intra-tumoral cellular heterogeneity of the original tissue, thus, they represent one of the best methods to study human cancers. The tumor microenvironment (TME) contains diverse immune cell populations, including innate lymphoid cells (ILCs), yet how stromal components influence cytokine-driven tumor–immune interactions remains unclear. Methods PDOs from CRC patients were used to screen TME-derived cytokines affecting tumor growth. Organoid-forming efficiency and signaling pathway activation were analyzed following cytokine stimulation in the presence or absence of CAFs. Tumor-infiltrating ILC subsets were characterized in patient samples, and co-culture systems were employed to assess cytokine production and stromal–immune interactions. Results IL-22 was identified as a cytokine that increased PDO-forming efficiency without activating fibroblasts. Although IL-22 typically signals through the JAK–STAT pathway, it unexpectedly activates MAPK signaling in PDO cells. Interestingly, interferon-γ (IFNγ) showed only partial cytotoxic effects on CRC cells. Tumor tissues contained both IFNγ-producing ILC1 and IL-22/IL-17A–producing ILC3 populations. Co-culture with PDOs selectively induced IL-22, but not IL-17A, production in ILC3 cells. Importantly, IL-22 enhanced organoid formation only in the absence of CAFs, whereas IFNγ activity was largely unaffected by stromal context. Discussion These findings demonstrate that CAFs modulate local immunity by selectively masking ILC3-derived IL-22 signaling while preserving ILC1-mediated IFNγ responses. This study emphasizes the importance of stromal context in interpreting cytokine function in CRC and reveals a previously unrecognized mechanism of stromal–immune crosstalk within the TME.
S. Hajdo, Z. Komlósi, B. Érsek et al.· Frontiers in Immunology· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
These findings identify a tumor-adapted MC state that orchestrates immune evasion and tissue remodeling during CRC progression, supporting the notion that MC are reprogrammed toward an immune-suppressive and pro-tumorigenic phenotype.
E. Putro, Alessia Carnevale, Caterina Marangio et al.· Cell Death & Disease· 0 citations