Tumor-Mimetic Microenvironment Primes Cancer Stemness and Drug Resistance through Nucleoskeleton-Mediated Chromatin Remodeling.

Mechanical regulation of m6A-dependent autophagy sustains cancer stemness and chemoresistance in a viscoelastic tumor microenvironment.

The mechanical properties of the tumor microenvironment fundamentally influence cancer progression, while how viscoelastic cues interface with epitranscriptomic regulation to control cell fate remains poorly understood. Here, a pair of hyaluronic acid-based supramolecular hydrogels with tunable network dynamics are engineered to mimic the viscoelastic properties of tumor ECM. Human osteosarcoma (HOS) cells encapsulated in highly dynamic (HD) hydrogels form compact spheroids, display elevated stemness markers, and exhibit enhanced metabolic activity compared to low-dynamic (LD) matrices. Mechanistic analysis reveals that HD hydrogels strengthen E-cadherin adhesion and activate an AMPK-N6-methyladenosine (m6A) methylation signaling cascade, which increases the translation of FOXO3 mRNA and drives autophagy. This mechanics-driven m6A-autophagy axis maintains self-renewal and promotes chemoresistance. In vivo, HD hydrogel-delivered spheroids exhibit enhanced tumor growth and chemoresistance, while autophagy inhibition markedly improves cisplatin efficacy against the grafted tumors. These findings establish viscoelasticity as a key upstream regulator of m6A-dependent autophagy in osteosarcoma and identify mechanical regulation of m6A modification on specific autophagy-related transcripts as a promising target for combination therapy.

Metabolic crosstalk between extracellular matrix, cancer-associated fibroblasts and tumor cells: drivers of tumor progression and therapeutic resistance.

This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.

Tumor plasticity in macrophage niches promotes dormancy, EMT and chemoresistance of non-small cell lung cancer stem cells

Macrophages are the major immune cell type in the microenvironment of non-small cell lung cancer (NSCLC), playing a key role in tumor development, progression, and response to therapies. Elucidating the interplay between macrophages and NSCLC is crucial to fulfill the potential of macrophage-targeting strategies. We used NSCLC surgical specimens to generate multicellular spheroids enriched in cancer stem cells (CSCs) and highly responsive to microenvironmental cues. NSCLC spheroids were used to characterize state transitions induced by macrophage-tumor cell interactions in terms of proliferation, epithelial-to-mesenchymal transition (EMT), expression of stemness-related factors, self-renewal, and drug resistance. To define whether state transitions were induced by cell–cell contact or soluble factors, we compared direct co-cultures of spheroids and macrophages with transwell cultures, where cells are separated by a porous membrane. Cellular interactions were recorded by time-lapse microscopy and immunofluorescence (IF), whereas EMT, dormancy, stemness and chemoresistance were evaluated by real-time PCR, immunoblotting and functional assays. We found that co-cultures allowing cell–cell contact, but not transwell cultures, induced robust state transitions in NSCLC CSCs, promoting a state of dormancy associated with increased stemness, EMT and chemoresistance. In direct co-cultures (named NIDO, for Niche-Induced DOrmancy), macrophages and tumor cells formed nest-shaped aggregates and underwent a specular modulation of TGF-β levels, suggesting a physical transfer of this cytokine from macrophages to NSCLC cells within cellular nests. Treatment with Bafilomycin A1, an inhibitor of autophagosome-lysosome fusion and autolysosome acidification, inhibited TGF-β relocation and prevented the full spectrum of TGF-β-induced state transitions, including chemoresistance, EMT, and nest formation. By contrast, antibody-mediated TGF-β neutralization had only a partial effect, indicating secretory autophagy as a key mechanism underlying macrophage-tumor cell interplay. Altogether, these results show that lung macrophages crucially influence CSC phenotype, proliferation, and therapy resistance, pointing to a key role of local cell circuits in regulating tumor cell plasticity.

PI3K Delta Inhibition Alters CD8 T Cell Différentiation and Reprograms the Tumor Microenvironment Following Adoptive Immunotherapy 2247548

PI3Kδ inhibition programs T cells with stemness and metabolic fitness that favor Tpex differentiation, resist terminal exhaustion, and remodel the TME toward an inflammatory state, supporting a practical strategy to improve ACT efficacy in solid tumors.

Hippo Pathway Regulation and Microenvironmental Cues Governing Human MSC Transition to Cancer‐Associated Fibroblasts

Cancer‐associated fibroblasts (CAFs) are key drivers of tumor progression. This study examined how three‐dimensional (3D) culture, hypoxia, and cancer‐derived soluble factors influence the transformation of human mesenchymal stem cells (hMSCs) into inflammatory CAFs (iCAFs). hMSCs from bone marrow, placenta, and chorion were cultured in 2D, in Matrigel‐based 3D systems, under hypoxia, and with soluble factors from colon cancer cells (HT29, HCT116). 3D culture strongly induced iCAF markers (IL1α, CSF3, IL6) while reducing myofibroblastic CAF markers (CCN2, MYL9, TAGLN). Hypoxia and cancer factors further enhanced this phenotype, promoting IL1α/IL6 secretion and shifting their influence from suppressing to stimulating cancer cell growth and angiogenesis. Mechanistically, these changes were associated with YAP/TAZ down‐regulation, and genetic depletion of YAP/TAZ alone was sufficient to convert hMSCs into iCAFs even in 2D culture. These findings highlight YAP/TAZ as critical regulators of hMSC‐to‐CAF transformation, with implications for therapeutic strategies targeting tumor stroma.

Integrated single-cell and spatial transcriptomic analyses reveal malignant epithelial glycolytic heterogeneity and spatial niche remodeling during colorectal cancer progression