Trends in cancer最新文献

Chimeric antigen receptor (CAR)-T cell therapy has reshaped cancer immunotherapy for hematological malignancies, yet progress in solid tumors remains limited. Physical barriers, antigen heterogeneity, and immunosuppressive tumor microenvironment restrict the activity and persistence of CAR-T cells, while safety concerns complicate target selection. Extending CAR technology to alternative immune lineages, such as macrophages, natural killer cells, tumor-infiltrating lymphocytes, and unconventional T cells, offers complementary mechanisms for tumor recognition, infiltration, and immune modulation. This review highlights recent advances in these emerging CAR platforms, compares their biological and translational features, and outlines how integrating cell-intrinsic properties with CAR design may guide the next generation of cellular immunotherapies for solid tumors.

The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from 'ecological buffering' by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.

Epigenetic dysregulation including frequent mutations in epigenetic regulators alongside nonmutational reprogramming driven by oncogenic and metabolic stresses represents a hallmark of pancreatic ductal adenocarcinoma (PDAC). Recent advances using low-input epigenomics and single-cell technologies have revealed their role in fostering cellular plasticity, stromal reprogramming, immune evasion, and therapy resistance. This review synthesizes current knowledge of epigenetic mechanisms in PDAC pathogenesis, highlighting their stage- and context-dependent roles in tumor progression, tumor microenvironment crosstalk, and metabolic adaptation. We further highlight emerging therapeutic strategies that target epigenetic vulnerabilities. By integrating cutting-edge epigenomic profiling with functional studies, we outline a roadmap for translating epigenetic discoveries into clinical strategies against this lethal malignancy.

Once viewed solely as degradative compartments, lysosomes shape cell fate through signaling, metabolism, and communication. In glioblastoma, their rewiring underlies plasticity, invasion, and resistance to therapies. This forum explores lysosomal dynamics in brain tumors and therapeutic strategies targeting lysosomal vulnerabilities, offering fresh perspectives for precision approaches in this lethal cancer.

Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These 'chimeroids' may enable scalable studies of cancer-microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis-tissue colonization. This review summarizes advances in stem cell-derived organoid models for organs frequently affected by solid tumor metastases, including the brain, lung, liver, and bone, and evaluates their ability to recreate physiologically relevant niches for studying cancer cell adaptation and colonization.

Interleukin 33 (IL33) in the tumor microenvironment of pancreatic cancer has been linked to both pro- and antitumor immune responses, suggesting a context-dependent role. Herein, we discuss the current understanding and challenges of therapeutically targeting IL33 signaling in pancreatic cancer.

Nectin-4 is an immunoglobulinlike cell adhesion molecule that contributes to tumor aggressiveness and immune evasion in pancreatic ductal adenocarcinoma (PDAC). Its high and selective expression on pancreatic cancer cells, together with the clinical efficacy of nectin-4-targeted antibody-drug conjugates in other solid tumors, establishes nectin-4 as a compelling therapeutic target in PDAC.

Reactive oxygen species (ROS) are essential second-messenger molecules, yet when deregulated, they fuel cancer growth and therapeutic resistance. In high-grade gliomas, including glioblastoma, diffuse hemispheric glioma, and diffuse midline glioma (DMG), genetic, epigenetic, and metabolic alterations drive chronic ROS production and redox imbalance. This oxidative stress promotes DNA damage, epigenetic reprogramming, tumor growth, and immune escape. In DMG, global DNA and histone hypomethylation are amplified by oxidative stress, while ROS-dependent Ras/Raf/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathways reinforce tumor survival. Paradoxically, the same ROS create an intrinsic vulnerability as excess ROS can overwhelm defenses and trigger cytotoxicity. Targeting ROS is challenging; however, new strategies, including NADPH oxidase inhibition, metabolic modulation, and ROS-inducing therapies, reveal vulnerabilities. Understanding this redox paradox is critical to exposing therapeutic vulnerabilities and improving outcomes for patients with these deadly cancers.

Ammonia acts as a metabolic checkpoint fueling regulatory T cells (Tregs). Gu et al. demonstrate that utilizing argininosuccinate lyase-linked survival buffering and a FOXP3-spermine-PPARγ axis for mitochondrial reinforcement allows Tregs to convert toxic waste into suppressive power, driving tumor immune evasion and immunotherapy resistance.

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. This milestone moment represents a long journey in FAKi development, from initial findings of limited single-agent activity to orally delivered FAKi effects that can sensitize solid tumors to chemotherapy, radiotherapy, and immunotherapy treatments. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.