A rapidly evolving frontier in cancer biology reveals the profound influence of exosomes on the tumor microenvironment (TME), particularly through their regulation of ferroptosis, a distinct form of iron-dependent cell death. Recent findings unravel how these nanoscale vesicles orchestrate complex intercellular communication, modulating cancer progression by altering cell phenotypes, suppressing immune responses, enhancing angiogenesis, remodeling the extracellular matrix, and ultimately driving metastasis and drug resistance. The crosstalk facilitated by exosome-mediated ferroptosis presents an intricate landscape where tumor cells and their surrounding stromal components converge, reshaping both local and systemic cancer dynamics.
Exosomes function primarily as couriers within the TME, delivering proteins, nucleic acids, and metabolites that recalibrate the signaling networks among tumor and non-tumor cells. This vesicle-mediated dialogue profoundly impacts ferroptosis pathways, influencing whether cells succumb to or survive oxidative death. Ferroptosis, characterized by the overwhelming accumulation of lipid peroxides and reactive iron, has become recognized as a pivotal determinant in cancer cell fate and immune cell function. The ways in which exosomes modulate ferroptosis have implications that extend well beyond cell-intrinsic outcomes, contributing decisively to tumor metastasis.
Metastasis, the dissemination of malignant cells to distant organs, remains the principal cause of cancer-related mortality worldwide. Intriguingly, evidence underscores the role of exosomes in pre-conditioning remote tissues to form pre-metastatic niches—a preparatory landscape that supports cancer cell colonization. Exosomal cargoes from cancer and stromal cells within the TME enact a series of molecular events that promote vascular permeability, immune suppression, and metabolic rewiring, all of which facilitate metastatic seeding. Notably, exosomes derived from nasopharyngeal carcinoma (NPC) cells release macrophage migration inhibitory factor (MIF), which reprograms macrophage ferroptosis and encourages their polarization towards a pro-tumorigenic M2 phenotype. This dual role—protecting certain immune cells from death while fostering immunosuppressive behavior—illustrates the nuanced interplay at work.
Additionally, hepatocellular carcinoma (HCC)-derived exosomes delivering miR-142-3p highlight a distinct mechanism whereby ferroptosis is induced in M1 macrophages, dampening their antitumor activities and aiding tumor invasion. This immunosuppressive orchestration extends further as platelet-derived extracellular vesicles elevate integrin β3 expression in NPC cells, which suppresses SLC7A11, fostering ferroptosis resistance within tumor cells and enabling bloodstream-mediated metastasis. Collectively, these insights illustrate how exosome-mediated regulation of ferroptosis within immune and tumor cells orchestrates a permissive milieu for the metastatic cascade.
The immunosuppressive dimensions of ferroptosis regulation introduce another layer of complexity in tumor-immune system dynamics. Ferroptosis sustains a delicate balance, where protective mechanisms in immunosuppressive cell types such as M2 macrophages, Tregs, and tumor-infiltrating neutrophils hinge on glutathione peroxidase 4 (GPX4) activity to prevent lipid peroxidation. Disrupting these defenses through ferroptosis induction can eliminate suppressive immune cells, unleashing antitumor responses. Paradoxically, ferroptosis can also impair effector immune populations, including CD8+ T cells, natural killer cells, and dendritic cells, weakening the immune system’s ability to fight tumors. The dichotomous nature of ferroptosis in immunity reveals a complex regulatory network that cancer cells exploit to evade destruction.
Increasingly, exosomes have emerged as critical modulators at this immunological crossroads. For example, NPC- and colorectal cancer (CRC)-derived exosomes inhibit ferroptosis in macrophages, skewing polarization towards immunosuppressive states that favor tumor progression. Similarly, cancer-associated fibroblast (CAF)-derived exosomes can elevate the labile iron pool in natural killer (NK) cells, inducing ferroptosis and consequently diminishing their cytotoxic capacity against tumors. These vesicle-mediated ferroptosis interactions substantially contribute to the establishment of an immunosuppressive TME, underscoring exosomes as pivotal agents in cancer immune evasion.
Beyond modulating immune landscapes, exosomes wield significant influence over tumor drug resistance—a formidable barrier in cancer therapy. Traditional resistance mechanisms involve alterations in drug transporters, target mutations, and adaptive signaling changes. Yet, emerging research illuminates the roles of exosome-mediated ferroptosis pathways in counteracting therapy efficacy. Exosomal transfer of regulatory RNAs and proteins affects ferroptotic sensitivity in cancer cells, thereby shaping their response to chemotherapy and radiotherapy. This revelation invites reconsideration of therapeutic strategies that integrate ferroptosis modulation.
A prime example includes CAF-derived exosomal miR-522, which impedes ferroptosis in gastric cancer cells by downregulating arachidonic acid lipoxygenase 15 (ALOX15), diminishing lipid ROS accumulation. This cascade reduces sensitivity to paclitaxel and cisplatin, two cornerstone chemotherapeutics. Contrarily, the long noncoding RNA DACT3-AS1, also secreted by CAFs, has demonstrated ferroptosis-promoting effects via the miR-181a-5p/SIRT1 axis, enhancing oxaliplatin sensitivity. The interplay between ferroptosis inhibitors and promoters via exosomal transfer illustrates the complexity of chemoresistance phenotypes.
In pancreatic cancer, the development of gemcitabine resistance is similarly tied to exosomal signaling. CAF-secreted miR-3173-5p suppresses acyl-CoA synthetase long-chain family member 4 (ACSL4), a driver of ferroptosis, to bolster chemoresistance. Moreover, pancreatic cancer cell-derived exosomes containing medium-chain acyl-CoA dehydrogenase (ACADM) phenotypically correlate with gemcitabine sensitivity, linking fatty acid metabolism alterations to ferroptosis evasion. Therapeutically, silencing ACADM enhances gemcitabine efficacy, emphasizing the translational potential of targeting ferroptosis regulators within exosomal cargo.
Lung cancer models reveal further insights where exosomes from cisplatin-resistant cells are enriched in miR-4443, which suppresses ferroptosis regulator FSP1 via inhibition of m6A RNA modification pathways. This exosome-mediated epigenetic modulation fosters ferroptosis resistance, propagating acquired chemoresistance. Targeting this axis, either by inhibiting exosome secretion or miR-4443 function, offers promising avenues to overcome treatment failure.
Interestingly, adipocyte-derived exosomes also contribute to chemotherapy resistance, notably in colorectal cancer. These exosomes release the microprotein MTTP, influencing the PRAP1/ZEB1 axis to elevate GPX4 while reducing ACSL4 expression. This suppresses lipid ROS generation, dampens ferroptosis, and promotes oxaliplatin resistance. The feedback amplification triggered by chemotherapy-induced MTTP upregulation creates a reinforcing loop exacerbating drug resistance, further complicating treatment landscapes.
Radiotherapy resistance also emerges under the influence of exosomes. Hypoxic conditions characteristic of solid tumors induce lung cancer cells to secrete exosomes bearing high levels of ANGPTL4. This protein amplifies expression of key ferroptosis-regulatory proteins such as GPX4, SLC11A7, and FTH4, mitigating lipid peroxidation and iron-dependent cell death pathways. The result is enhanced radioprotection for tumor cells, underscoring the multifaceted roles of exosomes in therapeutic resistance beyond chemotherapy.
Collectively, this growing body of evidence situates exosome-mediated ferroptosis regulation as a central axis in cancer progression, immune suppression, metastasis, and treatment resistance. The intricate interplay between vesicle cargoes, iron metabolism, lipid peroxidation, and cellular phenotypes forms a sophisticated regulatory network that tumor cells exploit. Therapeutically targeting exosome biogenesis, release, or cargo content to modulate ferroptosis presents an innovative and promising frontier in overcoming the pervasive challenges of cancer treatment.
Future directions beckon integration of ferroptosis induction strategies with immunotherapy and conventional modalities, potentially unlocking synergistic effects. Additionally, monitoring exosomal markers of ferroptosis regulators may serve as liquid biopsy candidates, offering predictive insights into metastasis risk and drug responsiveness. As the field advances, a deeper mechanistic understanding of exosome-ferroptosis crosstalk in specific cancer types will be critical for designing precision medicine approaches.
In essence, the emerging paradigm positions exosomes not merely as passive carriers but as active architects of the tumor microenvironment, leveraging ferroptosis pathways to stymie immune defenses, foster metastatic spread, and blunt therapeutic efficacy. This conceptual shift invites a reassessment of cancer biology through the lens of intercellular vesicle exchange, heralding novel diagnostic and therapeutic breakthroughs.
Subject of Research:
Exosome-mediated regulation of ferroptosis within the tumor microenvironment and its impact on cancer progression, metastasis, immunosuppression, and drug resistance.
Article Title:
Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application.
Article References:
Liu, N., Wu, T., Han, G. et al. Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application. Cell Death Discov. 11, 221 (2025). https://doi.org/10.1038/s41420-025-02484-y
Image Credits:
AI Generated
DOI:
https://doi.org/10.1038/s41420-025-02484-y
Tags: angiogenesis and tumor growthcancer progression and metastasisdrug resistance in tumorsexosome-mediated ferroptosisexosomes and immune response suppressionextracellular matrix remodeling in cancerferroptosis regulation mechanismsintercellular communication in tumorslipid peroxidation in cancer cellsnanoscale vesicles in cancer therapysignaling networks in tumor biologytumor microenvironment influence