Trends in Cancer

Illuminating cancer therapy via cryptic antigens A recent study in Science by Ely et al. identifies immunogenic, cancer-restricted noncanonical HLA-I-bound peptides (ncHLAp) in pancreatic cancer. Using a translation-informed filtering strategy, the study uncovers cryptic antigens derived from unannotated ORFs and validate antigen-specific T cell receptors (TCRs) capable of targeting pancreatic ductal adenocarcinoma (PDAC) in preclinical models, offering new avenues for immunotherapy.

Illuminating cancer therapy via cryptic antigens

Leveraging immunologically based therapies to treat diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas driven by distinct biological pathways. Although historically divided into two major subtypes on the basis of putative cell of origin, detailed genomic analyses have revealed additional classifications with prognostic implications. Additionally, the lymphoma microenvironment adds a layer of complexity distinct from genetic subclassifications and influences disease trajectory and response to therapies. Herein, we review the emerging roles of immune-based therapies to address this complex interplay between intrinsic genetic drivers and the surrounding tumor microenvironment in DLBCL.

Leveraging immunologically based therapies to treat diffuse large B-cell lymphoma

Bone appetite: bone-derived factors feed distant immune suppression The site of metastatic disease influences treatment response. A recent study in Cancer Cell by Cheng et al. revealed that bone metastases systemically impair immune function, abrogating immunotherapy response. Bone metastases led to osteopontin (OPN) production, which suppressed immunity in distal lesions. This highlights a novel cross-organ communication hindering antitumor immunity.

Bone appetite: bone-derived factors feed distant immune suppression

Platelets: tailoring metastasis treatment The dreadful liaison between platelets and tumor cells was discovered half a century ago. Since then, a plethora of studies have characterized the contribution of platelets to primary tumor development, survival of circulating tumor cells in the bloodstream, and metastatic seeding and outgrowth. Yet, although these provided a deep understanding of how platelets shape cancer progression, the field suffers from a lack of additional knowledge required to design efficient therapeutic strategies. Here, we aim to summarize recent discoveries that identify new ways in which platelets shape metastasis beyond their initial intravascular role. We further discuss platelet-borne molecular targets that could represent new avenues for therapeutically targeting platelets’ contribution to metastasis.

Platelets: tailoring metastasis treatment

Targeting TIM-3 to halt lung precancer progression Little is known about lung precancer progression. Recently, Zhu et al. explored the early immunologic landscape of lung adenocarcinoma (LUAD) precursors and identified T cell immunoglobulin and mucin domain 3 (TIM-3) as a putative immune checkpoint target for precancer interception. TIM-3 blockade in mice harboring premalignant lesions delayed progression to invasive adenocarcinoma, suggesting potential clinical utility in high-risk individuals detected through screening.

Targeting TIM-3 to halt lung precancer progression

Time-of-day dependency of adoptive cell therapies Adoptive cell therapies (ACTs), such as chimeric antigen receptor (CAR)-T cell therapy, have revolutionized cancer treatment, especially for hematological cancers. However, patient responses vary considerably. Emerging research reveals a striking influence of time of day (ToD) on ACT efficacy. Administering ACT during the early behavioral active phase enhances tumor control and reduces toxicity in preclinical models, an effect linked to the circadian clock. Latest clinical data also point to ToD effects in the cancer setting. In this opinion article we explore current insights and discuss the emerging underlying mechanisms. We propose that integrating ToD into clinical practice could represent a powerful yet easily implementable therapeutic regimen to improve efficacy and safety of ACT.

Time-of-day dependency of adoptive cell therapies

GDF15: from biomarker to target in cancer cachexia Most patients with advanced cancer suffer from cachexia, a complex metabolic disorder characterized by unintentional body weight loss that diminishes their quality of life and reduces the effectiveness of therapies. Currently, effective treatments for cachexia remain elusive. Growth differentiation factor 15 (GDF15) is a nonspecific blood biomarker of cancer, hyperemesis gravidarum, and various chronic diseases. GDF15 acts through GDNF family receptor α-like (GFRAL) receptors in the hindbrain to influence food intake, nausea, body weight, and insulin sensitivity. In this review we synthesize the current literature on the role of GDF15 in regulating metabolism and immunosuppression, and elucidate how these processes impact on cancer progression. We highlight recent clinical trials demonstrating that targeting GDF15 can overcome resistance to immunotherapy and increase physical activity, appetite, and weight gain in cancer patients.

GDF15: from biomarker to target in cancer cachexia

Extrachromosomal DNA: shaping the evolutionary dynamics of cancer Cancers are complex, diverse, and elusive, with extrachromosomal DNA (ecDNA) recently emerging as a crucial player in driving the evolution of about 20% of all tumors. In this review we discuss open questions concerning the evolutionary role of ecDNA in tumor development, including tumorigenesis and metastatic seeding, the mutational landscape on ecDNA, the dynamic ecDNA genotype–phenotype map, the structural evolution of ecDNA, and how knowledge of tissue-specific ecDNA evolutionary paths can be leveraged to deliver more effective clinical treatment. Looking forward, evolutionary theoretical modeling will be instrumental in advancing new research in the field, and we explore how modeling has contributed to our understanding of the evolutionary principles governing ecDNA dynamics. Ultimately, these challenges must be tackled to improve clinical stratification and create tumor- and patient-specific ecDNA-based therapies.

Extrachromosomal DNA: shaping the evolutionary dynamics of cancer

IL-18 revives dysfunctional CAR-T cells IL-18-armored chimeric antigen receptor (CAR)-engineered T (18.CAR-T) cells have demonstrated enhanced antitumor efficacy in lymphoma patients refractory to conventional CAR-T therapy. Unraveling the mechanisms behind this potent enhancement and mitigating associated toxicities could unlock a new era of next-generation CAR-T therapies with superior effectiveness and broader clinical impact.

IL-18 revives dysfunctional CAR-T cells

Pericyte phenotype switching in cancer Pericytes play an important physiological role as guardians of vascular integrity. In cancer, however, pericytes undergo profound phenotypic changes which foster tumor progression. Emerging transcriptomics and functional data provide evidence for a shift from quiescent to highly proliferating, matrix-secreting pericytes which destabilize the vasculature and create immune deserts. However, due to their inherent plasticity, proliferative tumor pericytes can be ‘coerced’ to switch back into a more quiescent and contractile state, a process which underpins durable tumor vessel normalization. Therapeutically, pericyte phenotype switching can be induced by targeting oncogenic, metabolic, or microtubule signaling pathways which induce Rho kinase activity. Thus, harnessing pericyte plasticity provides unique opportunities to synergize targeted anticancer therapies with immunotherapy.

Pericyte phenotype switching in cancer

Beyond safety: suicide systems in cell-based cancer therapies Cell-based therapies are promising for treating solid tumors, but challenges like tumor heterogeneity, antigen escape, and immunosuppressive microenvironments hinder their efficacy. Inducible suicide gene systems, often viewed solely as safety mechanisms, offer an underappreciated opportunity to enhance cellular therapies. These systems, triggered by various mechanisms (prodrugs, ligands, antibodies, or small molecules), enable controlled elimination of therapeutic cells. Recent developments demonstrate that this controlled cell death, especially when inducing immunogenic cell death (ICD), can kill even resistant tumor cells and reshape the tumor microenvironment (TME) from suppressive to stimulatory. This review highlights the transformative potential of integrating these suicide systems into cell therapies, overcoming key limitations, and amplifying antitumor responses while ensuring safety.

Beyond safety: suicide systems in cell-based cancer therapies

Advances in menin inhibition in acute myeloid leukemia Menin has emerged as a promising therapeutic target in acute myeloid leukemia (AML). The menin–MLL1 interaction promotes an oncogenic transcriptional program that drives leukemogenesis in HOX-mediated acute leukemias, including KMT2A-rearranged (KMT2Ar), nucleophosmin 1–mutated (NPM1m), and NUP98-rearranged (NUP98r) AML, prompting development of menin inhibitors for treatment of these subtypes. Successes in clinical investigation have led to recent FDA approval of revumenib for KMT2Ar AML, with numerous trials examining menin inhibitors as monotherapy and in combination with other antileukemic drugs ongoing. Although menin inhibitors represent a major advancement in AML treatment, acquired resistance is an evolving barrier to efficacy. Here, we examine the biological rationale for menin inhibition and discuss the landscape of clinical trials and resistance mechanisms associated with menin inhibitors.

Advances in menin inhibition in acute myeloid leukemia

mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.

mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression

Recharging aged-CAR with NAD+ to boost immunotherapy Impaired cellular metabolism contributes to the age-related decline in T cell function, undermining the response to immunotherapy in older patients with cancer. In a recent study, Hope et al. report that a reduction in intracellular NAD+ levels compromises metabolic fitness and drives immunosenescence. Notably, restoring NAD+ levels can reverse age-related chimeric antigen receptor (CAR)-T deterioration, suggesting a promising ‘metabolic immunotherapy’ that widely benefits older patients with cancer.

Recharging aged-CAR with NAD+ to boost immunotherapy

Transcriptional regulation of cuproptosis resistance in cancer therapy Cuproptosis is a newly identified form of copper-dependent cell death. Recent studies show that solid tumors evade this process through transcriptional reprogramming, including hypoxia inducible factor 1 subunit alpha (HIF1A) and NFE2 like BZIP transcription factor 2 (NFE2L2) activation and BTB domain and CNC homolog 1 (BACH1) suppression. Targeting these pathways may restore cuproptosis sensitivity, offering a promising strategy to overcome therapy resistance in cancer.

Transcriptional regulation of cuproptosis resistance in cancer therapy

Spliced to kill: RNA mis-splicing derived cancer neoantigens One of the major challenges in using neoantigen-based approaches in cancer treatment is the identification of cancer-specific neoantigens, particularly those that are shared by patients. In a recent report, Kim et al. uncover a novel source of cancer neoantigens in splicing factor mutant myeloid malignancies. These mis-spliced neoantigens offer new opportunities for engineered TCR–T cell therapies and neoantigen-based vaccines.

Spliced to kill: RNA mis-splicing derived cancer neoantigens

STEAP1: a promising target in prostate cancer therapy The unmet therapeutic need in prostate cancer (PCa), a disease that remains largely incurable after metastasis, underscores the urgency for new treatments. STEAP1 (six transmembrane epithelial antigen of prostate 1) is a cell surface protein highly expressed in >85% prostate tumors but shows little to no presence in normal tissues, making it a promising candidate for targeted therapy. Here, we summarize and discuss recent findings that underscore the promising role of STEAP1 in PCa therapy.

STEAP1: a promising target in prostate cancer therapy

Evolving role for eosinophils in cancer: from bench to bedside Eosinophils are increasingly recognized as important immune cells in the tumor microenvironment (TME). Recent technological advancements reveal their heterogeneity and complex context-dependent activities including the ability to elicit pro- or anti-tumorigenic effects. For instance, they can mediate cytotoxicity via highly eosinophil-specific granule proteins and reactive oxygen species, and contribute to antitumor immunity by interacting with various cells including T cells. Clinically, eosinophilia is often observed following various treatments including immunotherapy, where they may be beneficial for therapy. This Review explores eosinophil recruitment, immune interactions, therapeutic potential and methods for studying their activity. Understanding the role of eosinophils in the TME may lead to new therapeutic strategies and position them as targets or biomarkers in precision oncology.

Evolving role for eosinophils in cancer: from bench to bedside

Advancing cancer precision surgery with the tumor coagulome Solid tumors generate a local and systemic procoagulant state, placing cancer patients at risk of hemostatic complications. The interplay between the tumor coagulome, a tumor-intrinsic determinant, and surgery-induced coagulopathy may influence the risk of recurrence following complete surgical resection. Perioperative targeting of the coagulome could advance cancer precision treatment.

Advancing cancer precision surgery with the tumor coagulome

Thrilled to announce I'm moving to Manchester to lead the Cancer Origins group! If you're interested in how mutations and exposures drive tumourigenesis — come join the adventure

Ag(e)nostic precision oncology therapy approvals across the years Precision oncology leverages targetable molecular aberrations to treat cancer. Initially, use of these therapies required biomarker detection in a specific tumor type. Recently, regulatory agencies have approved highly active biomarker-based, tumor-agnostic therapies, which are crucial for the unmet needs of patients with rare cancer, including children with cancer, because an infrequent biomarker in an already rare cancer represents a prohibitive clinical trial accrual barrier. There are also now several ‘ag(e)nostic’ precision oncology therapies – agnostic to tumor type and also approved for all ages. In this opinion, we provide historical context for the precision oncology field and contend that, moving forward, ag(e)nostic precision oncology approvals should be the norm for this class of therapeutics rather than an exception to the rule.

Ag(e)nostic precision oncology therapy approvals across the years

The plasticity of cancer-associated fibroblasts The plasticity of cancer-associated fibroblasts (CAFs) refers to their ability to adopt a spectrum of distinct phenotypes or states in response to dynamic changes within the tumor microenvironment (TME). Recent advances in single-cell technologies have enabled detailed characterization of the heterogeneity and spatial complexity of CAF subpopulations across multiple tumor types. Notably, CAF subtypes undergo dynamic transitions during tumor progression and under therapy pressure. This review systematically summarizes the current knowledge on CAF plasticity shaped by both intrinsic and extrinsic factors, delineates research gaps, and highlights CAF phenotypic switching as a potential therapeutic opportunity.

The plasticity of cancer-associated fibroblasts

The extracellular matrix in cancer: from understanding to targeting Significant advances in matrix biology research have enhanced our understanding of individual matrix components and extracellular matrix (ECM) signalling. The dysregulation of the ECM during the development of solid tumours is a critical area of investigation. Despite recent progress, further investigation into the role of the ECM in cancer progression and therapeutic targeting remains essential for improving outcomes. This study is especially relevant for ECM-rich cancers, such as pancreatic cancer, which is characterised by dense fibrosis that impacts all stages of tumour development, including initiation, progression, and chemoresistance. Currently, no matrix-targeting agents have achieved mainstream clinical implementation. Challenges in this field include insufficient integration of new technologies, and limited understanding of cross disciplinary influences and of the complex, multifunctional nature of the ECM. In this review, we highlight key areas of matrix biology research that are crucial for advancing cancer treatment.

The extracellular matrix in cancer: from understanding to targeting

Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer - Nature Cancer Based on a proteogenomic analysis, Perreault and colleagues report that the majority of predicted tumor antigens originate from unmutated genomic sequences in melanoma and non-small cell lung cancer.

Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer
www.nature.com/articles/s43...

The extracellular matrix in cancer: from understanding to targeting Significant advances in matrix biology research have enhanced our understanding of individual matrix components and extracellular matrix (ECM) signall…

New review paper written by Jess Chitty in the team just out in Trends in Cancer (@cp-trendscancer.bsky.social) (OpenAccess)
The extracellular matrix in cancer: from understanding to targeting
| → www.sciencedirect.com/science/arti... ← |

Treatment of patients with pMMR GI cancers with tumor-infiltrating lymphocytes (TIL): a reality?

Dr. Yan-Ruide Charlie Li and our doctoral students Yichen John Zhu and Yuning Christine Chen cover "The clinical landscape of CAR-engineered unconventional T cells" and the amazing therapeutic potential it holds in their review for
@cp-trendscancer.bsky.social
doi.org/10.1016/j.tr...

Immunocytokines and cytokine neutralization for cancer immunotherapy

Harnessing technologies to unravel gastric cancer heterogeneity

Novel metabolic routes to cancer immune evasion The tumor microenvironment (TME) comprises heterogeneous cell types that closely interact with each other. Crosstalk among the TME components determines antitumor immune responses and their sensitivity to therapies such as immunotherapy. Recent studies published in Cancer Cell by Tang et al. and Zhu et al. identify two novel metabolic adaptations that tumors use to facilitate immune evasion. These targetable mechanisms suggest new avenues to improve antitumor immune responses.

Novel metabolic routes to cancer immune evasion