In this issue of Cancer Cell, Zhang et al. reveal that PAI-1-induced SFRP2high cancer-associated fibroblasts reduce the abscopal effect of radioimmunotherapy. Targeting PAI-1 or SFRP2 enhances T cell recruitment and prevents the formation of an immunosuppressive perivascular niche, improving radioimmunotherapy’s abscopal effect.

(Cancer Cell 40, 1044–1059.e1–e8; September 12, 2022)

(Cancer Cell 22, 91–105; July 10, 2012)

The mechanisms governing the progression of precursor lesions to invasive lung adenocarcinoma (LUAD) remain poorly understood. In this issue of Cancer Cell, Zhu et al. map the dynamic immune changes associated with this progression using high-resolution spatial mapping. Their identification of TIM-3 as a potential target may shift strategies for LUAD immunoprevention.

Tumor-associated macrophages (TAMs) are key players in tumor progression, yet their role in this process remains only partially understood. In this issue of Cancer Cell, Sheban et al. demonstrate that zinc finger E-box-binding homeobox 2 (ZEB2) acts as a master regulator that reprograms TAMs toward a pro-tumor phenotype and that therapeutic targeting of ZEB2 exhibits anti-tumor activity.

Despite recent advances in anti-cancer therapies, metastasis, especially to the brain, represents a major clinical challenge with rising incidences. In this issue of Cancer Cell, Xing et al. present a comprehensive transcriptomic map of the metastatic brain tumor environment at single-cell resolution.

Arginine availability and metabolism critically shape tumor-immune interactions. In this issue of Cancer Cell, Zhu et al. demonstrate that breast cancer-cell-derived arginine synthesized via ASS1 fuels macrophage polyamine synthesis, reinforcing immunosuppressive tumor-associated macrophages (TAMs). Mechanistically, this occurs through TDG/p53-dependent DNA demethylation and activation of PPARG.

Anti-PD-1 immune checkpoint inhibitors improve outcomes in relapsed/metastatic nasopharyngeal carcinoma (NPC). In this issue of Cancer Cell, Xu et al. achieved favorable outcomes by incorporating nivolumab into standard therapy for locally advanced NPC while removing chemotherapy from the radiation phase. This regimen offers a promising approach to reducing treatment-related toxicities.

In Cancer Cell, two studies unveil mechanisms by which co-option of the protein synthesis machinery promotes cancer progression and potential therapeutic interventions. Kuzuoglu-Ozturk et al. show that eIF4A-mediated enhancement of oncogenic transcript translation initiation drives cancer progression, while Weller et al. demonstrate how aberrant transfer RNA (tRNA) modification disrupts translational

T cells perform critical roles in orchestrating immunity in health and disease. However, decoding what individual T cells recognize has long been challenging due to the immense diversity of both T cell receptors (TCRs) and potential antigens. Recent advances in high-throughput TCR screening approaches now provide an opportunity to map the antigen specificity landscape of T cells with unprecedented

Early-life exposure to lifestyle-associated metabolic alterations could be a key contributor to early-onset colorectal cancer (EOCRC). Notably, insulin resistance (InsR)-linked hyperinsulinemia, elevated levels of insulin-like growth factors, and chronic inflammation could trigger EOCRC by modulating gene expression/pathways that support carcinogenesis/anti-apoptosis. Here, we discuss how InsR could

Tumor cell death shapes tumorigenesis and antitumor immunity in complex ways. Recently, Hänggi et al. revealed that necrotic-like death releases interleukin-1α (IL-1α), driving myeloid-mediated immunosuppression. Lamorte et al. demonstrated that medullary sinus macrophage (MSM) efferocytosis of apoptotic tumor cells activates the IL-33-regulatory T cell (Treg) axis, accelerating tumor growth. Blocking

In this issue of Cancer Cell, Teng et al. discover that small cell lung cancer and neuroendocrine prostate cancer highly express a circular RNA known as circRMST. They show that circRMST is necessary for these neuroendocrine cancers to promote their ASCL1-positive neuroendocrine phenotype through binding lineage transcription factors that promote ASCL1 expression.

Section snippets Main textOver the past five years, Cancer Cell has undergone a transformative evolution, reflecting the increasing multidisciplinary and integrative nature of cancer research. As editor-in-chief, it has been both a privilege and a profound responsibility to guide this journal through a period of significant change and growth, ensuring that it remains at the forefront of cancer research

This special issue of Cancer Cell is dedicated to “bridging the gap between foundational cancer biology and clinical oncology.” We asked scientists and clinicians to give us a brief “state of the field,” discussing the integration of new technologies, the importance of patient-centric approaches, the need for innovative clinical trial designs, and how fostering teamwork and inclusive research can help

Precision oncology has transformed cancer care but has barely benefited patients of diverse ancestry. Historically, self-reported race/ethnicity has served as a surrogate for biological differences, but genetic ancestry provides a more precise framework for understanding genetic drivers of cancer disparities, including associations between ancestry and tumor subtypes, and genetic variants affecting

While chimeric antigen receptor (CAR) T cell therapy has shown great success in hematologic malignancies, the effectiveness in solid tumors has been limited by several factors, including antigenic heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). In this review, we discuss the advancements made in clinical studies and challenges faced by CAR-T therapy for solid tumors

Artificial intelligence (AI) is increasingly being utilized in cancer research as a computational strategy for analyzing multiomics datasets. Advances in single-cell and spatial profiling technologies have contributed significantly to our understanding of tumor biology, and AI methodologies are now being applied to accelerate translational efforts, including target discovery, biomarker identification

Currently, no biomarker reliably predicts the efficacy of antibody-drug conjugates (ADCs). In this issue of Cancer Cell, Ma et al. present a predictive model for HER2-targeting ADC efficacy, incorporating immune-system components, hormone receptor status, clinical staging, and HER2+ cell proportion.

The Marathon of Hope Cancer Centres Network (MOHCCN), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities

Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses

All-trans retinoic acid (ATRA), a known regulator of hematopoiesis, is a key component of the established therapeutic regimen for treating acute promyelocytic leukemia (APL). In this issue of Cancer Cell, Mosialou et al. present a niche-based mechanism of ATRA targeting osteoblasts, repurposing ATRA treatment beyond APL.

Oncolytic viruses (OVs) are being optimized to treat cancer, including brain, ovarian, lung, and pancreatic tumors. Recent advances include replicating adenoviruses and herpes simplex virus 1 (HSV-1) armed with therapeutic transgenes, combined with serial injections and systemic delivery via retargeting, as achieved for adeno-associated virus 9 (AAV9). Clinical trials are showing promising efficacy

Precision oncology is predicated on the availability of robust biomarkers deployed at scale at the point of care. Although simple in conception, precision oncology often fails in practice because of the limitations of current diagnostic platforms, the emergence of drug resistance, and an incomplete understanding of cancer pathogenesis and the host immune response. Here, we discuss using real-world

In recent decades, we’ve witnessed tremendous advances in oncology with an increase in drug approvals across various modalities and indications, enabled by breakthroughs in personalized medicine, fundamental discoveries in cancer biology, advances in biotechnology, and the growing power of data science. Cancer, however, remains the leading cause of death worldwide, highlighting the need for a transformative

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results

New evidence published in Cell provides insight into the interplay between hypoxia-inducible factor activity and downstream neoantigen production in clear cell renal cell carcinoma (ccRCC). Jiang et al. show that HIF2α regulates expression of immunogenic human endogenous retroelements, with implications for antitumor immunity and immunotherapy responsiveness in ccRCC.

While immune checkpoint therapy (ICT) has revolutionized cancer treatment, most patients with advanced disease fail to achieve durable benefit. To address this challenge, it is essential to integrate mechanistic research with clinical studies to: (1) understand response mechanisms, (2) identify patient-specific resistance pathways, (3) develop biomarkers for patient selection, and (4) design novel

Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates

Current clinical trials are based on rigid designs and drug-centric approaches that can stifle flexibility and innovation. With advances in molecular biology and technology, there is an urgent call to revitalize trial designs to meet these evolving demands. We propose a reshaped, prismatic vision of clinical trials combining different knowledge layers, synergized with modern computational approaches

Melanoma brain metastasis (MBM) is associated with poor prognosis. In this issue of Cancer Cell, Rodriguez-Baena et al. identify nuclear factor κB (NF-κB) (Rela) as a driver of pro-tumoral microglia in MBM. While Rela deletion reprograms microglia, enhancing proinflammatory and anti-metastasis T cell responses, RELA activation in human macrophages correlates with immunotherapy resistance.

Cutaneous melanoma, frequently driven by BRAF (V600X) mutations, often develops resistance to mitogen-activated protein kinase (MAPK)-targeted therapies and immune checkpoint inhibitors. In this issue of Cancer Cell, Lubrano et al. identify RhoA-FAK-AKT signaling as a resistance mechanism and demonstrate that combining RAF-MEK glue with a FAK inhibitor enhances tumor regression and immune response

In this issue of Cancer Cell, Zhang et al. use single-cell RNA sequencing to compare immune cell dynamics in triple-negative breast cancers treated with the PD-L1 inhibitor atezolizumab plus paclitaxel or nab-paclitaxel. They identify distinct T cell activation patterns and highlight mast cells’ role in immune activation exclusively in the nab-paclitaxel combination.

In this issue of Cancer Cell, Palmer et al. describe the discovery and preclinical testing of the first-in-class CDK4-selective inhibitor atirmociclib. By sparing CDK6, atirmociclib has the potential to ameliorate dose-limiting hematological toxicities that limit drug exposure and treatment continuity and, by extension, the antitumor efficacy of dual CDK4/6 inhibitors.

The therapeutic efficacy of chimeric antigen receptor (CAR) T cells is compromised in antigen-low tumors due to poor sensitivity and insufficient persistence. In this issue of Cancer Cell, Pham-Danis et al. design the ALA-CART platform to improve CAR T cell sensitivity, persistence, differentiation, and cytotoxic function by enhancing LAT phosphorylation after low antigen stimulation.