In this issue of Cancer Cell, Qiu et al. use single-cell metabolic analysis to identify reduced mannose metabolism as a previously unknown feature of exhausted T cells. This metabolic pathway can be targeted to enhance memory and persistence of adoptively transferred T cells, resulting in improved anti-tumor efficacy.

Liquid biopsy has received tremendous attention as a non-invasive approach for detecting and tracking cancer. Here, we discuss the latest work on circulating tumor DNA and circulating tumor cells with respect to clinical applications, including cancer screening, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms.

Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches

Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked

Circadian disruption increases cancer risk, but connections between circadian clocks and cancer biology are diverse and depend on tumor type. In this issue of Cancer Cell, Gonzalez-Aponte et al. demonstrate that circadian timing of glucocorticoid exposure affects glioblastoma growth. These findings underscore the importance of timing in designing therapeutic interventions.

The heterogeneity of urothelial carcinoma (UC) and variable treatment responses poses significant clinical challenges. In this issue of Cancer Cell, Hamidi et al. conducted a multi-omics analysis of 2,803 UC patients from four clinical trials with anti-PD-L1, revealing four transcriptional subtypes. This approach could help tailor therapies for UC.

The role of myeloid cells in tumor immunity is multifaceted. While dendritic cells support T cell-mediated tumor control, the highly heterogenous populations of macrophages, neutrophils, and immature myeloid cells were generally considered immunosuppressive. This view has led to effective therapies reinvigorating tumor-reactive T cells; however, targeting the immunosuppressive effects of macrophages

(Cancer Cell 1, 269–277; April 2002)

Section snippets Main textCancers are conventionally classified as “hot” tumors that are associated with high tumor mutation burdens (TMBs) and tumor-infiltrating immune cells or “cold” tumors associated with a dearth of neoantigens and immune cell exclusion.1 This dichotomy is frequently used to define the degree of pre-existing immune cell reactivity within the tumor microenvironment and has been

Aggressive features of hepatocellular carcinoma (HCC) are highly related to liver tumor-initiating cells (TICs), which are heterogeneous and plastic. In this issue of Cancer Cell, Yang et al. reveal the ability of CD49f-high TICs in shaping the tumor immunosuppressive microenvironment in HCC.

Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. find that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.

(Cancer Cell 42, 1919–1935.e9; November 11, 2024)

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.

Harrold et al. evaluate the fertility impact of checkpoint inhibitor blockade (ICB), demonstrating that unlike in utero exposure, post-exposure conception appears to result in uncomplicated pregnancies and healthy progeny. They demonstrate contemporaneous monitoring of temporal female hormonal fluctuations before, on, and post ICB exposure and prior to successful embryo implantation.

An ideal cell surface target has ubiquitously high cancer expression, absence from healthy tissues, and an essential role cancer initiation and/or maintenance. In this issue of Cancer Cell, Hamilton et al. combine proteomics, transcriptomics, epigenomics, and dependency databases to identify DLK1, a novel immunotherapeutic target for neuroblastoma.

In this issue of Cancer Cell, MacFawn et al. reveal that tertiary lymphoid structures (TLSs) in high-grade serous ovarian cancer (HGSOC) vary significantly by anatomical site. They highlight a distinct stromal composition associated with TLS formation, with cancer-educated mesenchymal stem cells (CA-MSCs) inversely linked to TLS activity and patient prognosis.

Pre-clinical data suggest that increased circulating growth differentiation factor 15 (GDF15) is a cause of both anorexia/cachexia syndromes and hyperemesis gravidarum in pregnancy, serious conditions with no highly effective treatment. A phase 2 study of a therapeutic GDF15 monoclonal antibody in the New England Journal of Medicine suggests that effective treatment of anorexia/cachexia in cancer may

Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice.

The role of B cells in cancer remains incompletely understood. Three recent publications, including a study by Fitzsimons et al. in this issue of Cancer Cell,1 use single-cell RNA sequencing to define pan-cancer atlases of tumor-infiltrating B cell subsets, paving the way for profound advances in our understanding of B cell-dependent antitumor immunity.

We compare the clinical trial success rates of products receiving US Food and Drug Administration (FDA) accelerated approval (AA) to those approved without using this pathway. Our findings raise important questions about how the AA pathway can best optimize early access to therapeutics that are ultimately proven safe and effective.

Lactylation, a recently identified post-translational modification, has initially been linked to gene transcription regulation through epigenetic mechanisms. However, its role in tumorigenesis—whether as a major driver or a minor regulator—remains uncertain. Here, we summarize the current understanding of lactylation and discuss the inherent challenges in definitively attributing specific biological

According to the widely accepted “three Es” model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel “three Cs”

Microscopic examination of cells in their tissue context has been the driving force behind diagnostic histopathology over the past two centuries. Recently, the rise of advanced molecular biomarkers identified through single cell profiling has increased our understanding of cellular heterogeneity in cancer but have yet to significantly impact clinical care. Spatial technologies integrating molecular

Gliomas exhibit significant molecular diversity and poor prognosis. In this issue of Cancer Cell, Curry et al. apply Patch-seq on human glioma samples uncovering hybrid cells with glial and neuronal features, capable of firing action potentials in isocitrate dehydrogenase mutant gliomas. These findings highlight the importance of neural features in tumor biology and progression.

Despite aging being one of the strongest risk factors for cancer, little is known about the biological mechanisms that promote tumor initiation. In this issue of Cancer Cell, Yan et al. address this fundamental question in the context of breast cancer and report that midkine is upregulated during the aging process and can promote tumorigenesis.

In this issue of Cancer Cell, Gao et al. map fibroblast diversity across tumors and chronic inflammatory tissues. The authors uncover universal fibroblast subtypes such as LRRC15+ and MMP1+ myofibroblasts along with specialized tissue-specific subtypes. They reveal cellular roles of fibroblasts in immunosuppression through stromal niches and cell-cell interactions.

The ability of disseminated cancer cells to colonize the brain is highly dependent on initial survival cues, often evoking early microenvironmental adaptations. In this issue of Cancer Cell, Gan et al. unveil disparate tumor architectures in early stage HER2+ breast cancer and triple-negative breast cancer brain metastases that shape stromal interactions, providing a rationale for subtype-dependent

Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. Given the histologic and molecular heterogeneity of OC, we will focus on high-grade serous carcinoma (HGSC). Here, we provide a critical and more holistic view of the evidence supporting various routes of metastasis, including

γδT cells represent a group of immune cells that are understudied but whose utility has been recognized for cancer immunotherapy purposes. Recent studies have highlighted a critical role for these cells in tumor initiation, growth, and metastasis and revealed an increasingly complex biology of γδT cell subsets that is context and tissue specific. We discuss here how γδT cell subsets are regulated,

Cancer-associated fibroblasts (CAFs) are heterogeneous and ubiquitous stromal cells within the tumor microenvironment (TME). Numerous CAF types have been described, typically using single-cell technologies such as single-cell RNA sequencing. There is no general classification system for CAFs, hampering their study and therapeutic targeting. We propose a simple CAF classification system based on single-cell

Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of Cancer Cell, Wang et al.1 report dynamics and transcriptional states of CD8+ T cell clones over time in patients treated with anti-PD-1, anti-CTLA-4, or a combination of the two. These findings have important implications for understanding and monitoring combination immunotherapy