In the intricate landscape of cancer biology, the tumor microenvironment (TME) emerges as a dynamic and multifaceted arena where cancer stem cells (CSCs) coexist and interact with a myriad of other cellular components. This environment is an ecosystem comprising not only CSCs but also non-CSC tumor cells, immune effectors, cancer-associated fibroblasts (CAFs), endothelial cells, the extracellular matrix (ECM), and a complex network of signaling molecules. Together, they orchestrate the progression and maintenance of tumors through sophisticated biochemical dialogues. Central to this dialogue are exosomal non-coding RNAs (ncRNAs), which have recently been unveiled as potent mediators that facilitate communication between non-CSCs and CSCs, critically influencing the stemness and malignancy of the latter.
CSCs share defining characteristics with normal stem cells, including the remarkable ability to self-renew, proliferate indefinitely, and differentiate into diverse tumor cell lineages. The preservation of these stem-like traits is essential for sustained tumor growth, metastasis, and resistance to therapies. Intriguingly, exosomal ncRNAs originating from various sources within the TME, notably the non-CSC tumor cells, have emerged as pivotal regulators that uphold CSC stemness by modulating the genetic and signaling landscape of these crucial cells. This modulation occurs through a targeted influence on genes and pathways intimately linked to stem cell maintenance, underscoring a complex regulatory circuitry that supports CSC vitality.
The role of exosomal ncRNAs in this context is multi-dimensional. Tumor-derived exosomes laden with ncRNAs have been documented to upregulate fundamental stemness markers, including CD44, CD133, OCT4, Sox2, and Nanog across a spectrum of cancers such as pancreatic, oral squamous cell carcinoma, colorectal, osteosarcoma, and nasopharyngeal carcinoma. This upregulation not only perpetuates the stem cell-like state of CSCs but also amplifies their invasive and metastatic potential, along with enhancing resistance to chemotherapeutic agents. Such findings signify that exosomal ncRNAs are critical drivers of aggressive tumor phenotypes and therapeutic recalcitrance via stemness augmentation.
Beyond tumor cells, mesenchymal stem cells (MSCs) residing within the TME exert a profound influence on CSC biology through their secretion of exosomes rich in ncRNAs. MSCs boast intrinsic high plasticity and an adaptive secretome responsive to environmental cues. Bone marrow-derived MSCs (BM-MSCs), for instance, release exosomal microRNAs like miR-155, which inhibit apoptosis and promote proliferation in multiple myeloma cells, concomitantly upregulating key stemness markers and drug resistance proteins. Similarly, BM-MSC-derived miR-142-3p has been shown to activate the Notch signaling pathway by modulating downstream targets such as CD133 and Lgr5, thereby bolstering CSC populations and their stem-like attributes in various cancers.
CAFs, an integral cellular component of the TME, further contribute to CSC stemness modulation via exosomal ncRNA transfer. Under hypoxic conditions, CAFs co-cultured with pancreatic cancer cells elevate the expression of stemness proteins including CD44, CD133, OCT4, and Sox2, leading to a marked increase in CSC populations and enhanced tumor resistance. Additional research has revealed that CAF-derived exosomes carrying circHIF1A act as molecular sponges for miR-580-5p within breast cancer cells, subsequently upregulating CD44 and cultivating stem-like traits that favor tumor progression. These findings shine a spotlight on the essential role of CAFs in remodeling CSC behavior through exosomal ncRNA-mediated communication.
Immune cells embedded in the TME also participate actively in shaping CSC stemness. M2 macrophage-derived exosomes, for example, are replete with miR-27a-3p, which targets thioredoxin-interacting protein (TXNIP) to promote liver CSC maintenance and activation. By manipulating immune signaling pathways, these exosomal ncRNAs facilitate CSC survival and proliferation, illustrating a nuanced mechanism through which immune components within the TME can indirectly sustain tumor aggressiveness.
At the molecular signaling level, exosome-mediated delivery of ncRNAs exerts a decisive influence on several stemness-related pathways crucial for CSC maintenance. The Wnt/β-catenin pathway is a prime example, serving as a linchpin in the self-renewal and undifferentiated state of CSCs. Studies in non-small cell lung cancer have identified long non-coding RNAs such as PKMYT1AR that interact with miR-485-5p to activate this canonical pathway, reinforcing stemness and facilitating tumor initiation. Concurrently, in lung adenocarcinoma, miR-1275 amplifies both Wnt/β-catenin and Notch signaling axes, jointly fostering a stem cell-like phenotype and promoting aggressive disease progression.
Notch signaling itself stands as a critical conduit in the regulation of CSC proliferation, maintenance, and resistance to chemotherapy. Research underscores that exosomal ncRNAs like miR-600 suppress KLF6 expression, resulting in increased Notch1 transcriptional activity which supports stemness and metastatic dissemination in ovarian cancer cells. Such modulation reveals a sophisticated mechanism by which CSCs exploit exosomal ncRNA cargo to fine-tune their self-renewal signaling programs and evade therapeutic pressure.
The PI3K/Akt pathway represents another signaling cascade modulated by exosomal ncRNAs that enhances CSC characteristics. Through intricate regulation of key downstream transcription factors, microRNAs regulate ovarian and endometrial CSC self-renewal and differentiation, maintaining malignant potential. Further complexity is introduced by CAF-secreted miR-146a-5p, which activates STAT3 and mTOR pathways in urothelial bladder cancer, augmenting CSC stemness and resistance to chemotherapeutic agents. Such multifaceted signaling modulation reinforces the central role of exosomal ncRNAs in driving oncogenic pathways that sustain CSCs.
Breast cancer models provide additional insights, where tumor-secreted exosomes enriched with miR-378a-3p and miR-378d target negative regulators such as Numb and DKK3. This targeting leads to activation of the EZH2/STAT3 axis, a pathway intimately tied to CSC maintenance and chemotherapy resistance. These findings demonstrate how ncRNAs can orchestrate a wide array of molecular programs to bolster tumor aggressiveness via continuous support of CSC populations.
Collectively, this body of research underscores the pivotal role of exosomal non-coding RNAs as critical molecular messengers that orchestrate the bidirectional communication between non-CSCs and CSCs. Through the modulation of gene expression and activation of multiple converging signaling pathways, these ncRNAs sustain the stemness phenotype critical for tumor persistence and progression. Therapeutic strategies aimed at targeting these exosomal ncRNAs or their downstream pathways hold tremendous promise for disrupting CSC-driven tumor resilience and improving clinical outcomes.
Advancing this field demands a deeper mechanistic understanding of exosomal ncRNA biogenesis, cargo selection, and cellular uptake dynamics within the TME. Moreover, the heterogeneity of exosomal populations and their context-specific effects highlight the necessity for precision medicine approaches aimed at selectively modulating harmful exosomal signaling without disrupting physiological communication. As research continues to unravel these complex networks, new biomarkers and therapeutic targets for combating cancer stemness and therapy resistance are poised to emerge.
In conclusion, the evolving landscape of cancer research places exosomal non-coding RNAs at the forefront of our understanding of tumor biology. Their ability to mediate intercellular crosstalk between diverse cellular constituents of the tumor microenvironment and regulate the fundamental stemness characteristics of cancer stem cells offers a paradigm-shifting perspective. Harnessing this knowledge could pave the way for innovative diagnostic and treatment modalities that specifically dismantle the molecular foundations of cancer persistence and aggressiveness.
Subject of Research:
Exosomal non-coding RNAs as regulators of cancer stem cell stemness within the tumor microenvironment.
Article Title:
Exosomal non-coding RNAs: mediators of crosstalk between cancer and cancer stem cells.
Article References:
Wang, S., Shu, J., Wang, N. et al. Exosomal non-coding RNAs: mediators of crosstalk between cancer and cancer stem cells. Cell Death Discov. 11, 434 (2025). https://doi.org/10.1038/s41420-025-02726-z
Image Credits:
AI Generated
DOI:
https://doi.org/10.1038/s41420-025-02726-z
