Lung cancer is the leading cause of cancer-related deaths worldwide. Chemotherapy is associated with side effects, such as damage to myeloid cells and a reduction in the number of immune cells in patients. In addition, tumor cells hijack the mitochondria of immune cells through tunnel nanotubes, thereby weakening immune ability.

In this study the effects of direct mitochondria transplantation on cancer cell proliferation and chemotherapeutic sensitivity were determined, as well as anti-tumor immunity in in vitro and in vivo lung cancer models.

A combination of mitochondrial transplantation and cisplatin chemotherapy was shown for the first time to significantly improve immune infiltration of advanced non-small cell lung cancer (NSCLC) and overcome the shortcomings of cisplatin chemotherapy, including damage to myeloid cells and a reduction in the number of immune cells.

The findings of the current study provide valuable recommendations for enhancing immune infiltration and augmenting anti-tumor efficacy during chemotherapy in advanced NSCLC. In addition, the findings support “mitochondrial transfer” as a novel paradigm in tumor treatment.

The objective of the current study was to evaluate the chemosensitizing capacity of auranofin (AF), a gold (I) complex traditionally used in rheumatoid arthritis treatment, in potentiating the cytotoxic effects of doxorubicin (DOX) in melanoma cell models, specifically drug-sensitive (B16F10) and multidrug-resistant (B16F10/ADR) variants.

Experimental measurements, including in vitro cytotoxicity and apoptosis assays, surface plasmon resonance (SPR), immunoblotting assays, as well as theoretical calculations, such as molecular docking and molecular dynamics (MD) simulations, were used to systematically delineate the interaction dynamics between AF and thioredoxin reductase 1 (TrxR1). The anti-tumor efficacy of co-treatment with AF and DOX was assessed by examining cell viability and apoptotic rates.

Co-treatment with AF and DOX significantly increased anti-tumor efficacy, as evidenced by reduced cell viability and increased apoptotic rates. This synergistic effect was attributed to inhibition of TrxR1 by AF, which compromised tumor cell antioxidant defenses and elevated intracellular reactive oxygen species (ROS), thereby enhancing apoptotic pathways. Notably, AF treatment mitigated the heightened TrxR activity in DOX-resistant cells, intensifying the pro-oxidant effects of DOX, leading to increased ROS production and cell death. The data also showed that AF binds with high affinity to the selenocysteine residue within the catalytic site of TrxR1, which partially overlapped with the binding site of the endogenous substrate, thioredoxin (Trx), but with greater avidity. This unique binding configuration impedes the reduction of Trx by TrxR1, triggering an apoptotic response in cancer cells.

This study underscores the chemosensitizing potential of AF in overcoming multidrug resistance in cancer therapy through redox modulation. The molecular mechanism of action underlying AF on TrxR1 demonstrated the unique binding configuration that impedes the reduction of Trx by TrxR1 and instigates an apoptotic response in cancer cells. These findings pave the way for the clinical application of AF as a chemosensitizer, offering a novel approach to augment the efficacy of existing chemotherapy regimens.

Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis (BCBM).

Migrasomes were isolated and purified from BCBM cells (231-BR) and non-specific organotropic parental counterparts (MDA-MB-231), specifically designated as Mig-BCBM and Mig-BC, respectively. The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model. The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR, western blotting, immunofluorescence, ex vivo fluorescence imaging, and a series of rescue experiments.

Mig-BCBM potently augmented the permeability of vascular endothelial layers, which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro. The administration of Mig-BCBM significantly disrupted the blood-brain barrier (BBB) and accelerated BCBM progression in vivo, as evidenced in mouse models, compared to the Mig-BC and control groups. Mechanistically, Mig-BCBM harbored ATF6, a critical transducer of endoplasmic reticulum (ER) stress. Upon internalization into hCMEC/D₃ cells, ATF6 elicited robust ER stress responses, culminating in downregulation of ZO-1 and VE-cadherin. Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.

This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis, suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.