Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.

Sandén et al. report that the ligand signaling lymphocyte activation molecule family member 6 protects acute myeloid leukemia cancer cells from T cell-mediated killing, leading to immune escape, and show that this can be targeted by a blocking antibody.

Trowbridge and colleagues provide a comprehensive review of clonal hematopoiesis in diverse cancer settings, from myeloid malignancies to solid tumors, covering underlying molecular and cellular mechanisms and exploring therapy-related approaches.

Using mouse pancreatic cancer models, Tsanov et al. show that reactivation of SMAD4 at metastatic sites promotes tumor growth in the lung through RUNX1 but restrains metastatic growth through KLF4 in the liver, influenced by organ-specific epigenetic states.

Han et al. show that SMARCA5 is required for the sustained expression of genes required for malignancy in pancreatic cells with mutant KRAS. Inhibiting SMARCA5 activity prevents malignant transformation while maintaining pancreatic regeneration.

Wang and colleagues report the clinical results and immunological correlates of a phase 2 clinical trial of cryoablation plus lenvatinib and sintilimab in persons with advanced or metastatic intrahepatic cholangiocarcinoma.

Tao et al. show that SCRN1 acts as a scaffold to facilitate GPX4 phosphorylation by STK38, thereby preventing chaperone-mediated autophagy of GPX4 and subsequent ferroptosis in patient-derived organoids and mouse models for hepatocellular carcinoma.

Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.

Qian and colleagues show that MEF2D⁺ cancer precursors reprogram liver-resident Kupffer cells to create a microenvironment supporting liver tumorigenesis.

Zhao et al. used single-cell and spatial multiomics data analysis of human and mouse lung adenocarcinoma tumors and cell lines to reveal TP53 mutation-associated changes in cancer cells and their microenvironment.

Investment continues as the field awaits phase 3 readouts for next-generation radioligand therapies in 2026.

Propelled by a growing understanding of nasopharyngeal carcinoma pathogenesis through elucidation of its genomic and immune landscape, therapy has progressed from radiotherapy alone to combined chemotherapy and immunotherapy. This Clinical Outlook focuses on recent milestones and future directions for patients with nasopharyngeal carcinoma.

Ron DePinho received his MD from the Albert Einstein College of Medicine and completed his medical and postdoctoral training at Columbia University. He was the founding director of the Belfer Center at the Dana-Farber Cancer Institute. As president of the University of Texas MD Anderson Cancer Center, he launched the Cancer Moonshot initiative. He currently serves as a professor of cancer biology at the MD Anderson Cancer Center and was elected to the National Academies of Sciences and Medicine. He is the co-founder of several biotech companies and an advocate for innovation-driven healthspan solutions for the underserved.