Mitochondrial fitness is critical for effector CD8+ T cell responses against cancer. In this issue of Cancer Cell, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.

The heterogeneity of breast cancers and the availability of several therapeutic options requires prognostic and predictive tools for tailoring adjuvant treatments. In this issue of Cancer Cell, Denkert et al. analyze longitudinal gene-expression data from the Penelope-B trial and identify five adaptive clusters with independent prognostic value to established signatures.

In this issue of Cancer Cell, Acha-Sagredo et al. reveal an interferon-high immunophenotype in colorectal cancer that predicts responsiveness to immune checkpoint inhibitors across both mismatch repair-deficient and mismatch repair-proficient subtypes. They identify CD74 as a biomarker and establish the importance of epithelial interferon levels in regulating immune responses.

Squamous cell cancers (SCCs) of the head and neck, esophagus, and lung, referred to as aero-upper digestive SCCs, are prevalent in the United States and worldwide. Their incidence and mortality are projected to increase at alarming rates, posing diagnostic, prognostic, and therapeutic challenges. These SCCs share certain epigenetic, genomic, and genetic alterations, immunologic properties, environmental

(Cancer Cell 40, 88–102; January 10, 2022)

The mechanisms underlying synergy between checkpoint blockade and anti-angiogenic therapy remain elusive. In this issue of Cancer Cell, Guo et al. analyze hepatocellular carcinoma patients treated with anti-PD-1 and lenvatinib, identifying a circulating CD8+ T cell population critical for treatment efficacy. Engaging these cells could enhance immunotherapy across other settings.

In this issue of Cancer Cell, Ellrott et al. present machine learning models to classify samples into The Cancer Genome Atlas molecular subtypes using compact sets of genomic features. These validated, ready-to-use models are publicly available, although some clinical hurdles need to be cleared before they are fully implemented.

Plasma cells (PCs) are the main producers of antibodies and have context-dependent roles in tumor immunity. In this issue of Cancer Cell, Gao et al. report that intratumoral PCs drive maintenance of glioblastoma stem cells to promote tumor growth via IgG secretion that activates a FcγRIIA-SYK-AKT signaling axis.

In this issue of Cancer Cell, Son et al. highlight an unexpected role for skin β-papillomaviruses in the protection against skin carcinogenesis. T cell immunity to skin papillomaviruses blocks the expansion of p53 mutant clones in ultraviolet (UV) radiation-damaged skin, preventing the development of skin cancer.

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

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.

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

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.

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

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.