In this phase 2 trial, Perez et al. reported the safety of the vitamin D receptor agonist paricalcitol with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma and the pharmacodynamic effects of paricalcitol in fibroblasts and immune cells.

Wong et al. uncover a nutritional dependency for acute lymphoblastic leukemia cells that spread to the central nervous system and propose using copper restriction to impair leukemia progression by disrupting nucleotide synthesis through the inhibition of electron transport chain activity.

Gabrilovich and colleagues provide an overview of myeloid cell plasticity during differentiation, within the tumor microenvironment and in response to therapy, and discuss the challenges to therapeutic targeting of myeloid cells in cancer.

Ahmed and colleagues show that, by promoting ‘dressing’ of intact tumor target antigens onto dendritic cells, tumor irradiation enhances chimeric antigen receptor T cell persistence and efficacy in lung metastasis models.

Wong et al. uncover a nutritional dependency for acute lymphoblastic leukemia cells that spread to the central nervous system and propose using copper restriction to impair leukemia progression by disrupting nucleotide synthesis through the inhibition of electron transport chain activity.

In this phase 2 trial, Perez et al. reported the safety of the vitamin D receptor agonist paricalcitol with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma and the pharmacodynamic effects of paricalcitol in fibroblasts and immune cells.

Ahmed and colleagues show that, by promoting ‘dressing’ of intact tumor target antigens onto dendritic cells, tumor irradiation enhances chimeric antigen receptor T cell persistence and efficacy in lung metastasis models.

Castro-Dopico et al. report the design of reagents to bridge F-actin and Fcγ receptors, endowing a range of antigen-presenting cells with the ability to cross-present antigens from dead tumor cells and boosting antitumor immunity in preclinical models.

Tang et al. identify cysteinyl leukotriene receptor 1 (CysLTR1) as a critical regulator of tumor-induced myelopoiesis, suggesting CysLTR1 targeting to sensitize tumors to immune checkpoint blockade.

Zhao and colleagues show that CD300ld, upregulated in pathologically activated neutrophils, mediates contact-dependent suppression of cytotoxic CD8⁺ T cells by binding to phosphatidylserine, inhibiting antitumor immune responses.

The capacity of tumors to progress and evade therapeutic intervention is driven largely by their remarkable plasticity and cellular heterogeneity. Our Series on Tumor Heterogeneity and Plasticity provides a holistic view of the current status of this fast-paced field.

As tumor resistance to ADCs grows, new payloads are being investigated — from decades-old agents to newer drug classes such as immunotherapies and radioligands.

Eytan Ruppin received his MD and PhD from Tel Aviv University, where he started his lab in 1995, conducting computational multi-disciplinary research. In 2018, he moved to the US National Cancer Institute as the chief of its Cancer Data Science Lab, before recently moving to the Translational Research Institute at Cedars-Sinai. His research is focused on AI approaches to advance precision oncology, and developing low-cost biomarkers for cancer treatment responses.

Elaine Fuchs is renowned for her research in skin biology, stem cells and associated disorders, including cancers and inflammation, and has published over 380 articles. She received her PhD in biochemistry from Princeton University, did postdoctoral research in cell biology at MIT, and has been on the faculty at the University of Chicago and now Rockefeller University. Her awards include the National Medal of Science, L’Oréal-UNESCO Award, the International Society for Stem Cell Research (ISSCR) Innovation Award, the Canada Gairdner International Award and the Franklin Medal. She is a member of the National Academy of Sciences, National Academy of Medicine, American Philosophical Society, Pontifical Academy of Sciences, and the Royal Society.

Angela Nieto received her PhD from Universidad Autónoma in Madrid in 1987. After short postdoctoral stays in Madrid and at the Max Planck Institute for Psychiatry in Munich, she joined the National Institute for Medical Research in London in 1989 and returned to Spain in 1993 to lead a research group at the Cajal Institute. She moved to the Neurosciences Institute in Alicante in 2004 as full professor and head of developmental neurobiology. She currently leads the cell plasticity in health and disease program and coordinates the Spanish National Research Council Cancer Hub.

As we do every December, we revisit the highs and lows of the past year in a dedicated Focus issue of commissioned comment, news and highlights from the primary research literature.