Research

Liver metastases are difficult to treat owing to the liver’s metabolically active and immune-tolerant environment. We discovered that metastatic cancer cells exploit liver-derived palmitate to evade neutrophil-mediated immune surveillance through DHHC17-dependent stabilization and secretion of laminin-511. Targeting this pathway suppresses liver metastasis growth and restores neutrophil-mediated cancer cell killing, uncovering a metabolically driven mechanism of innate immune evasion in the liver. Vandekeere et al, Nature Metabolism, 2026

Colorectal cancer (CRC) liver metastases exhibit distinct histopathological growth patterns associated with markedly different outcomes, yet no therapies specifically target poor-prognosis replacement metastases. We discovered that liver steatosis promotes poor prognosis replacement metastasis formation by stablizing MYC via acetylation leading to increased proline fueled collagen synthesis. These findings provide a mechanistic explanation for the emergence of poor-prognosis liver metastases and identify potential patient stratification criteria and therapeutic targets. Peng-Winkler et al, Nature, 2026

In many cancers, acetylation -which controls how genes are turned on and off- is aberrantly active. Drugs against acetyltransferases and deacetylases are currently investigated in clinical and pre-clinical studies, but we still do not fully understand how the expression of these enzymes themselves is regulated. In this study, we focused on acetyltransferase KAT2A. We discovered that the expression of KAT2A in cancer cells is controlled by palmitoylation through a multistep signaling cascade. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases. Liu M et al, Nature Cell Biology, 2026

Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer-derived metastases. We discovered that cancer cells recruit lung resident AT2 cells as lipid feeder cells using spatial mass spectrometry imaging on lung tissues of mice and patients with breast cancer. Consequently, targeting the lipid synthesis of AT2 cells was sufficient to impair lung metastasis growth in mice without apparent adverse effects. Thus, this work may foster the use of spatial metabolomics data to identify novel therapeutic strategies against cancer metastasis and beyond. Liu X-Z et al, Cancer Discovery, 2026

Aspartate is a metabolite that is very low in blood. This has let to the notion that cancer cells de novo produce aspartate for DNA, RNA and protein synthesis. We discovered that breast cancer patients have higher pulmonary aspartate levels compared to patients without a cancer. Moreover, we find that pulmonary aspartate increases the aggressiveness of lung metastases because it acts as a ligand for the NMDA receptor. In turn, a calcium-dependent signaling cascade activates the unusual translation initiation and elongation factor eIF5A by hypusination, which leads to the activation of an alternative translational program in the cancer cells boosting their aggressiveness. This mechanism can be targeted with clinically approved drugs. Doglioni et al, Nature 2025

Most cancer cells do not survive in distant organs, like seeds that fall on inhospitable soil. This changes in the presence of a primary tumor, but why? Our current understanding is that primary tumors alter the extracellular matrix and immune environment of distant organs. However, we discovered that primary breast tumors increase the concentration of lipids in distant organs by communicating with resident cells and that this enables the arriving cancer cells to grow into metastases. Specifically, we observed that tumor secreted factors rewired lung resident alveolar type II (AT2) cells to release more palmitate. In turn, disseminated breast cancer cells use the extra palmitate to active pro-metastatic NFkB signaling. Altea-Manzano et al, Nature Cancer, 2023.

Cancer cells reprogram their metabolism as they travel to distant organs to establish metastases, the leading cause of cancer-related mortality. Although the metabolic state of primary tumors has been extensively studied, the specific metabolic alterations associated with metastases have only recently garnered significant attention. The metabolic dependencies that arise during the metastatic cascade, along with the adaptive metabolic shifts required for growth in a new microenvironment, present promising therapeutic targets. In this review, we provide an overview of cancer metabolism, followed by a detailed exploration of the metabolic changes occurring at each stage of metastasis and within common organs of metastatic spread. Finally, we examine the potential and challenges of targeting metabolic pathways in cancer therapy. Peng-Winkler & Fendt, Physiological Reviews, 2026

Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumor metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterization of metabolic heterogeneity in tumors. In addition to the metabolic heterogeneity observed in primary tumors, metabolic heterogeneity temporally evolves along with tumor progression. In this review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment. Demicco et al., Nature Metabolism, 2024