Mitochondria are organelles with double-membrane structure of inner and outer membrane, which provides main energy support for cell growth and metabolism. Reactive oxygen species (ROS) mainly comes from mitochondrial and can cause irreversible damage to cells under oxidative stress. Thus, mitochondrial homeostasis is the basis for maintaining the normal physiological function of cells and mitophagy plays a pivotal role in the maintenance of mitochondrial homeostasis. At present, to enhance the sensitivity of cancer cells to radiotherapy and chemotherapy by regulating mitochondria has increasingly become a hot spot of cancer therapy. It is particularly important to study the effect of ionizing radiation (IR) on mitochondria and the role of mitophagy in the radiosensitivity of cancer cells. Most of the existing reviews have focused on mitophagy-related molecules or pathways and the impact of mitophagy on diseases. In this review, we mainly focus on discussing the relationship between mitophagy and radiosensitivity of cancer cells around mitochondria and IR.

Background We analyzed the relationship among peripheral blood lymphocytes, exposed sternum and vertebra body bone marrow (BM), and overall survival (OS) to find BM dosimetric parameters of lymphopenia during chemoradiotherapy (CRT) for patients with esophageal squamous cell carcinoma (ESCC). Methods We examined 476 ESCC patients from January 2012 to January 2015, all of whom received concurrent or sequential CRT. Absolute lymphocyte counts (ALC) during radiotherapy (RT) of each patient were collected from the routine workup at the following RT times: pretreatment ALC (ALC0), at 1–5, 6–10, 11–15, 16–20, and 21–25, and more than 26 sessions (called ALC1–6, respectively). The sternum and vertebral body BM were delineated in accordance with uniform standards, and the irradiated volumes were calculated by dose-volume histograms (DVH). The Kaplan–Meier method and Cox proportional hazards regression were used to analyze the survival of the patients. Comparisons of DVH were performed using the Mann–Whitney U test or two-sample t-test where appropriate. Results A relative volume of sternum BM irradiated by more than 20 Gy could clearly affect the peripheral blood lymphocytes. The V20 of sternum BM and V50 of vertebra body BM were related to the OS of the patients, and the level of ALC2 (at 6–10 times of RT) could predict the outcomes of patients. The Cox regression analyses showed that the 218 patients with ALC2 ≥ 0.8 × 10⁹/L had a significantly higher OS (47.0 months vs. 30.9 months, p < 0.0001) than the 258 patients with ALC2 < 0.8×10⁹/L. Conclusion In patients with ESCC, the relative volume of sternum BM irradiated by more than 20 Gy was associated with lymphocytes. Patients with ALC2 ≥ 0.8 × 10⁹/L had a significantly higher OS. The V20 of the sternum BM, the V50 of the vertebra body BM, and the level of ALC2 were significant prognostic factors in patients with ESCC.

Objectives: Cancer cells with ‘stemness’ are generally resistant to chemoradiotherapy. This study aims to compare the differences in radiation sensitivity of A549 and CD44⁺A549 stem-like cells to X-rays and carbon ion radiation (C-ions), and to find a target that can kill cancer stem-like cells (CSCs) of non-small cell lung cancer (NSCLC). Methods: The study used two cell lines (A549 and CD44⁺A549). The tumorigenicity of cells was tested with animal experiments. The cells were irradiated with X-rays and C-ions. Cell viability was detected using the CCK-8 and EdU assay. A liquid chromatograph-mass spectrometer (LC–MS) helped detect metabolic differences. Protein and mRNA expression were detected using a Western blot, reverse transcription-quantitative (RT-qPCR), and PCR array. The autophagic activity was monitored with a CYTO-ID^® Autophagy Detection Kit 2.0. Immunofluorescence and co-immunoprecipitation helped to observe the localization and interaction relationships. Results: First, we verified the radio-resistance of CD44⁺A549 stem-like cells. LC-MS indicated the difference in autophagy between the two cells, followed by establishing a correlation between the radio-resistance and autophagy. Subsequently, the PCR array proved that TGM2 is significantly upregulated in CD44⁺A549 stem-like cells. Moreover, the TGM2 knockdown by small interfering RNA could decrease the radio-resistance of CD44⁺A549 cells. Bioinformatic analyses and experiments showed that TGM2 is correlated with the expression of CD44 and LC3B. Additionally, TGM2 could directly interact with LC3B. Conclusions: We established the CD44-TGM2-LC3 axis: CD44 mediates radio-resistance of CD44⁺A549 stem-like cells through TGM2 regulation of autophagy. Our study may provide new biomarkers and strategies to alleviate the radio-resistance of CSCs in NSCLC.

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. 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. 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. 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. Not applicable.