Restoring mitochondria enhances immune response against lung cancer

While chemotherapy remains a cornerstone of lung cancer treatment, it often weakens the immune system it relies on for long-term control. Now, researchers have found a way to turn this weakness into strength—by transplanting healthy mitochondria into the tumor environment. In advanced non-small cell lung cancer (NSCLC), combining mitochondrial transplantation with cisplatin not only enhanced immune cell infiltration but also reversed tumor metabolism and improved the drug's effectiveness. This innovative approach transforms mitochondria from mere energy suppliers into active allies in cancer therapy, showing potential to reshape how we treat aggressive lung tumors.

Lung cancer causes more deaths than any other cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Chemotherapy is the first-line treatment for advanced NSCLC, yet its effectiveness is hampered by toxic side effects and emerging resistance. Moreover, chemotherapy damages immune cells and reduces their presence in the tumor microenvironment, limiting long-term control. Adding to this challenge, tumors can hijack immune cell mitochondria through nanotube-like structures, further dampening immunity. Immunotherapy has improved outcomes for some, but many patients still fail to respond. Due to these limitations, there is a pressing need for strategies that restore immune power and metabolic balance during chemotherapy.

Researchers from Tongji University School of Medicine and Nantong University published a study (DOI: 10.20892/j.issn.2095-3941.2024.0596) in Cancer Biology & Medicine that introduces a novel approach to lung cancer therapy. They investigated whether direct mitochondrial transplantation could enhance the effects of chemotherapy in advanced NSCLC. By combining functional mitochondria with cisplatin, the team aimed to not only improve tumor response but also restore immune vigor inside the tumor microenvironment. Their findings mark a significant step toward integrative treatments that energize both cells and immunity.

The researchers isolated functional mitochondria from human cardiomyocytes—cells known for their high energy output—and transplanted them into NSCLC tumor models, both in vitro and in vivo. Alone, mitochondrial transplantation did not harm cancer cells, but when combined with cisplatin, it significantly amplified tumor suppression. This synergy reduced the IC₅₀ of cisplatin from 12.93 μM to 6.7 μM, indicating greater drug sensitivity. Tumors in mice shrank more dramatically with the combination therapy than with chemotherapy alone, and immune infiltration markedly increased. Transcriptomic analysis revealed a striking shift in tumor metabolism: downregulation of glycolysis and hypoxia genes, and upregulation of oxidative phosphorylation pathways—reversing the Warburg effect. Markers of cell proliferation (Ki67, P53) and stemness (HIF-1α, CD44, CD133) were suppressed. Importantly, mitochondrial transplantation also restored mitochondrial activity in immune cells, enhancing the function of T cells and natural killer (NK) cells. The treatment caused no additional toxicity and preserved body weight and organ integrity. This work demonstrates that mitochondria can serve as metabolic and immunologic reinforcements, transforming the tumor landscape into one more susceptible to immune attack and chemotherapy.

This research introduces a powerful dual-action strategy. By replenishing immune cells with functional mitochondria, we are not just enhancing their energy—but restoring their ability to fight. At the same time, tumor cells become more vulnerable to chemotherapy. It's like rearming the immune system while disarming the tumor. This could be a promising avenue for patients who don't respond well to conventional treatment."

Dr. Liuliu Yuan, lead investigator of the study

This discovery lays the groundwork for a new therapeutic paradigm—one that leverages the mitochondria's unique biology to augment cancer treatment. In patients with advanced NSCLC, mitochondrial transplantation could enhance the effects of existing chemotherapy drugs while minimizing immune suppression. Beyond lung cancer, this approach may extend to other tumors where immune dysfunction and metabolic reprogramming are barriers to treatment success. With further refinement and clinical trials, mitochondrial transfer could evolve into a versatile platform for combination therapies, helping clinicians push past the current limits of cancer care and into a new era of bioenergetic and immune restoration.