Frontiers in immunology · 2026
Integrating multi-omics data reveals IL-8 positive cancer-associated fibroblasts as mediators of chemotherapy-induced tumor progression in breast cancer.
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Liao Huifeng, Li Huayan, Song Jin, Dong Junhua, Bai Xue
Аннотация
BACKGROUND: Recent studies have shown that while chemotherapy kills tumor cells, it may also induce adaptive changes in cells within the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which could paradoxically promote tumor progression. This study aimed to investigate the role of CAFs exposed to paclitaxel (PTX) or doxorubicin (DOX) in tumor progression and explore the underlying mechanisms.
METHODS: We examined the effects of PTX- or DOX-exposed CAFs on tumor migration and invasion through in vitro experiments. Bioinformatics analyses including Mendelian randomization, BayesPrism, and scPagwas were performed to elucidate the clinical relevance of IL-8 + CAFs in breast cancer. Additionally, in vitro experiments were conducted to confirm the tumor-promoting effects of CAFs-derived IL-8 and explore the underlying molecular mechanisms.
RESULTS: Our findings showed that CAFs exposed to PTX or DOX further promoted tumor migration and invasion compared to untreated CAFs. Notably, PTX and DOX significantly increased IL-8 expression levels in CAFs, suggesting that IL-8 may be a key cytokine mediating the tumor-promoting effect of CAFs exposed to chemotherapeutic agents. Interestingly, this tumor-promoting effect could be partly reversed by reparixin, an IL-8 receptor inhibitor. Mendelian randomization analysis confirmed that both IL-8 eQTL and plasma IL-8 levels were significantly associated with breast cancer risk. Further insights from BayesPrism and scPagwas indicated that IL-8 + CAFs were associated with clinical prognosis and may play a critical role in breast cancer progression. Furthermore, we confirmed the tumor-promoting effect of CAFs-derived IL-8. Mechanistically, IL-8 may modulate apoptosis by activating the NF-κB pathway, thereby inhibiting tumor cell apoptosis and leading to chemoresistance. Clinically, high IL-8 expression correlated with chemoresistance and poor survival in breast cancer patients.
CONCLUSION: Our study suggests that the upregulation of IL-8 in CAFs following PTX or DOX treatment may contribute to chemotherapy-mediated tumor progression. These findings provide potential avenues for improving chemotherapy outcomes.
METHODS: We examined the effects of PTX- or DOX-exposed CAFs on tumor migration and invasion through in vitro experiments. Bioinformatics analyses including Mendelian randomization, BayesPrism, and scPagwas were performed to elucidate the clinical relevance of IL-8 + CAFs in breast cancer. Additionally, in vitro experiments were conducted to confirm the tumor-promoting effects of CAFs-derived IL-8 and explore the underlying molecular mechanisms.
RESULTS: Our findings showed that CAFs exposed to PTX or DOX further promoted tumor migration and invasion compared to untreated CAFs. Notably, PTX and DOX significantly increased IL-8 expression levels in CAFs, suggesting that IL-8 may be a key cytokine mediating the tumor-promoting effect of CAFs exposed to chemotherapeutic agents. Interestingly, this tumor-promoting effect could be partly reversed by reparixin, an IL-8 receptor inhibitor. Mendelian randomization analysis confirmed that both IL-8 eQTL and plasma IL-8 levels were significantly associated with breast cancer risk. Further insights from BayesPrism and scPagwas indicated that IL-8 + CAFs were associated with clinical prognosis and may play a critical role in breast cancer progression. Furthermore, we confirmed the tumor-promoting effect of CAFs-derived IL-8. Mechanistically, IL-8 may modulate apoptosis by activating the NF-κB pathway, thereby inhibiting tumor cell apoptosis and leading to chemoresistance. Clinically, high IL-8 expression correlated with chemoresistance and poor survival in breast cancer patients.
CONCLUSION: Our study suggests that the upregulation of IL-8 in CAFs following PTX or DOX treatment may contribute to chemotherapy-mediated tumor progression. These findings provide potential avenues for improving chemotherapy outcomes.