Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5–1% of intestinal neoplasms; they are found in 0.3–0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.

This review comprehensively analyzes the current landscape of tumor-agnostic therapies in oncology. Tumor-agnostic therapies are designed to target specific molecular alterations rather than the primary site of the tumor, representing a shift in cancer treatment. We discuss recent approvals by regulatory agencies such as the FDA and EMA, highlighting therapies that have demonstrated efficacy across multiple cancer types sharing common alterations. We delve into the trial methodologies that underpin these approvals, emphasizing innovative designs such as basket trials and umbrella trials. These methodologies present unique advantages, including increased efficiency in patient recruitment and the ability to assess drug efficacy in diverse populations rapidly. However, they also entail certain challenges, including the need for robust biomarkers and the complexities of regulatory requirements. Moreover, we examine the promising prospects for developing therapies for rare cancers that exhibit common molecular targets typically associated with more prevalent malignancies. By synthesizing these insights, this review underscores the transformative potential of tumor-agnostic therapies in oncology. It offers a pathway for personalized cancer treatment that transcends conventional histology-based classification.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components—such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines—contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes.

Hepatocellular carcinoma (HCC) has an increasing incidence and global mortality burden. Diagnosis and management of HCC has improved over the years, and innovative molecular tests are emerging as promising biomarkers for prognosis and response prediction. Conventional circulating protein biomarkers, such as alpha-fetoprotein, are widely used but have limited sensitivity and specificity. Liquid biopsy approaches rely on the detection and characterization of additional blood-borne analytes—including circulating tumor-derived DNA genomic or epigenomic features, exosomes, circulating tumor cells, and others. These methods—potentially in combination with conventional blood-based analytes—have the potential to significantly improve early detection, prognostication, and treatment monitoring. In this review, we highlight recent nongenomic blood-based liquid biopsy approaches and their clinical applications in HCC.