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Background <p>Head and neck adenoid cystic carcinoma (HNACC) is an uncommon but aggressive salivary gland malignancy with high recurrence and metastasis rates. Its “immune-cold” phenotype limits the efficacy of systemic therapy, and thus, radiotherapy is the principal treatment for unresectable cases. However, frequent radioresistance suggests the involvement of distinct molecular drivers. This study investigated the role of CCL5 in HNACC radioresistance, its mechanistic link to autophagy, and its potential as a radiosensitization target.</p> Methods <p>Transcriptome sequencing of radiation-sensitive (SACC-83) and radiation-tolerant (SACC-LM) cell lines, integrated with GEO datasets, identified candidate genes. For functional validation, genetic manipulation and pharmacological inhibition with the CCL5/CCR5 antagonist maraviroc were performed. Cellular proliferation, invasion, apoptosis, cell cycle, and radiosensitivity were assessed. Autophagy was examined by transmission electron microscopy and western blotting, with a focus on AMPK/mTOR signaling. A xenograft mouse model was used to evaluate the therapeutic effect of maraviroc combined with radiotherapy.</p> Results <p>CCL5 expression was elevated in radioresistant cells and further induced by irradiation. High CCL5 levels promoted proliferation, migration, and invasion while reducing radiation-induced apoptosis and G₂/S arrest. Mechanistically, CCL5 activated AMPK, suppressed mTOR, and enhanced autophagy, supporting cell survival under radiation stress. CCL5 inhibition reduced autophagy, restored radiosensitivity, and synergized with irradiation, whereas autophagy activation reversed these effects. In vivo, maraviroc combined with radiotherapy decreased tumor burden, suppressed CCL5 expression, and inhibited autophagy.</p> Conclusion <p>CCL5 promotes radioresistance in HNACC through maintenance of AMPK/mTOR-dependent autophagy. Targeting the CCL5/CCR5 axis enhances radiosensitivity and represents a promising therapeutic strategy.</p> Clinical trial number <p>Not applicable.</p>

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CCL5 improves radiation resistance through activation of the AMPK/mTOR pathway in adenoid cystic carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Mingyu Tan,
  • Yanliang Chen,
  • Jinxin Yang,
  • Qian Wang,
  • Lu Li

摘要

Background

Head and neck adenoid cystic carcinoma (HNACC) is an uncommon but aggressive salivary gland malignancy with high recurrence and metastasis rates. Its “immune-cold” phenotype limits the efficacy of systemic therapy, and thus, radiotherapy is the principal treatment for unresectable cases. However, frequent radioresistance suggests the involvement of distinct molecular drivers. This study investigated the role of CCL5 in HNACC radioresistance, its mechanistic link to autophagy, and its potential as a radiosensitization target.

Methods

Transcriptome sequencing of radiation-sensitive (SACC-83) and radiation-tolerant (SACC-LM) cell lines, integrated with GEO datasets, identified candidate genes. For functional validation, genetic manipulation and pharmacological inhibition with the CCL5/CCR5 antagonist maraviroc were performed. Cellular proliferation, invasion, apoptosis, cell cycle, and radiosensitivity were assessed. Autophagy was examined by transmission electron microscopy and western blotting, with a focus on AMPK/mTOR signaling. A xenograft mouse model was used to evaluate the therapeutic effect of maraviroc combined with radiotherapy.

Results

CCL5 expression was elevated in radioresistant cells and further induced by irradiation. High CCL5 levels promoted proliferation, migration, and invasion while reducing radiation-induced apoptosis and G₂/S arrest. Mechanistically, CCL5 activated AMPK, suppressed mTOR, and enhanced autophagy, supporting cell survival under radiation stress. CCL5 inhibition reduced autophagy, restored radiosensitivity, and synergized with irradiation, whereas autophagy activation reversed these effects. In vivo, maraviroc combined with radiotherapy decreased tumor burden, suppressed CCL5 expression, and inhibited autophagy.

Conclusion

CCL5 promotes radioresistance in HNACC through maintenance of AMPK/mTOR-dependent autophagy. Targeting the CCL5/CCR5 axis enhances radiosensitivity and represents a promising therapeutic strategy.

Clinical trial number

Not applicable.