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Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer. Cancer cells adopt a series of strategies to evade the immune response mounted by the organism against them. Here we find that tumour cells can hijack mitochondria from immune cells by forming physical nanotubes, and suggest that inhibiting this process might represent a potential immunotherapy approach.

Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases de novo synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement of human LDHA with rabbit LDHA, which is relatively resistant to OAA inhibition, eliminated the paradoxical correlation between the elevated PKM2 activity and the decreased lactate concentration in cancer cells treated with a PKM2 activator. Furthermore, rabbit LDHA-expressing tumours, compared to human LDHA-expressing tumours in mice, displayed resistance to the PKM2 activator. These findings describe a mechanistic explanation for the PKM2 paradox by showing that OAA accumulates and inhibits LDHA following PKM2 activation. Wiese et al. find that oxaloacetate generated through increased activation of PKM2 can inhibit lactate dehydrogenase A, shedding light on the long observed PKM2 paradox during Warburg metabolism in cancer cells.

The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8

The tumor microenvironment (TME) is a unique metabolic niche that can inhibit CD8+ T cell metabolism and cytotoxic activity. It has been a challenge to dissect the metabolic interplay between tumors and T cells. Consequently, the mechanisms whereby the TME regulates CD8+ T cell function are not completely understood. Here we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as a direct inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the tricarboxylic acid (TCA) cycle in CD8+ T cells. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1), a G-protein coupled cell surface receptor. This leaves CD8+ T cells reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates (anaplerosis). In contrast, lactate reduces PC-mediated anaplerosis, thus depleting the TCA cycle and reducing SUCNR1 signaling. Notably, inhibition of pyruvate dehydrogenase (PDH) is sufficient to override lactate-mediated reprogramming, and to restore PC activity, succinate secretion, and autocrine activation of SUCNR1 both in vitro and in vivo using syngeneic tumor models. Thus, dissecting the CD8+ T cell-specific metabolic adaptation to the TME unexpectedly revealed that a TCA cycle succinate shunt and plasticity in pyruvate flux is a crucial determinant of CD8+ T cell anti-tumor activity. Furthermore, we identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-rich TME. These studies demonstrate that the TME remodels CD8+ T cell pyruvate metabolism, leading to a reduction in CD8+ T cell cytotoxicity and anti-tumor immunity.

As one of the fundamental requirements for cell growth and proliferation, nitrogen acquisition and utilization must be tightly regulated. Nitrogen can be generated from amino acids and utilized for biosynthetic processes through transamination and deamination reactions. Importantly, limitations of nitrogen availability in cells can disrupt the synthesis of proteins, nucleic acids and other important nitrogen-containing compounds. Rewiring cellular metabolism to support anabolic processes is a feature common to both cancer and proliferating immune cells. In this review, we will discuss how nitrogen is utilized in biosynthetic pathways and highlight different metabolic and oncogenic programs that alter the flow of nitrogen in order to sustain biomass production and growth - an important emerging feature of cancer and immune cell proliferation.

Summary How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2 + breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2 + cell lines in culture and in xenografts. Finally, we show that cyclocreatine in combination with the HER2 kinase inhibitor lapatinib reduces the growth of a trastuzumab-resistant HER2 + patient-derived xenograft. These findings suggest that activation of the phosphocreatine energy shuttle by MtCK1 Y153 phosphorylation creates a druggable metabolic vulnerability in cancer.