The premetastatic niche is a specialized microenvironment established by tumor cells prior to the formation of metastatic foci in distant organs. This niche provides an optimal landing site for circulating tumor cells. As key mediators of intercellular communication, exosomes play a pivotal role in shaping the premetastatic niche. This review analyzes the effects of exosomes on premetastatic niche formation from multiple perspectives, including angiogenesis, metabolic reprogramming, matrix remodeling, immune response, organicity, and epithelial-mesenchymal transition (EMT). Their value in tumor diagnosis, prognosis, and treatment, as well as the challenges and opportunities for future clinical transformation are discussed. This article presents a narrative review conducted in accordance with the SANRA guidelines.

NTRK gene fusions are oncogenic drivers for a variety of adult and pediatric tumors, making them a target for tumor-agnostic precision medicine. Tropomyosin receptor kinase (TRK) inhibitors are approved by the US Food and Drug Administration for cancers driven by TRK fusions. However, NTRK genes can fuse with many different partner genes, leading to diverse TRK fusion proteins, highlighting the importance of identifying the specific fusion partner with optimal pan-cancer diagnostics. This analysis aims to provide an updated descriptive compendium of NTRK gene fusions.

NTRK gene fusions were identified via literature searches (PubMed), a search of a clinical trials database (larotrectinib), and searches of two genomic databases (Memorial Sloan Kettering and Children's Hospital of Philadelphia).

In total, 358 distinct NTRK gene fusion-tumor pairings were identified across 25 tumor types. Primary CNS tumors were observed to harbor 86 distinct NTRK gene fusions, followed by sarcomas (n = 73). Overall, 229 different fusion partners were identified across tumor types (regardless of NTRK gene). Twenty-three fusion partners were found to fuse with >1 NTRK gene across tumor types, while 183 fusion partners were associated with only a single NTRK gene in one tumor type. ETV6::NTRK3 was found in the highest number of different tumor types.

This analysis illustrates the diversity of NTRK gene fusion partners across various tumor types and highlights the importance of selecting a pan-tumor fusion-partner agnostic test that can identify both known and novel fusion partners to identify patients who may benefit from treatment with TRK inhibitors.

Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection has become a strong prognostic stratification factor in postoperation non-small cell lung cancer (NSCLC). Here, we sought to investigate the guiding potential of MRD in informing adjuvant therapy (AT) decisions.

Patients with stage IA to IIIB NSCLC who had undergone confirmed R0 resection were enrolled. Blood samples were collected 1 month after surgery before initiation of AT (landmark) and longitudinally every 3-6 months since surgery. Postoperative AT was conducted according to the guideline recommendations, and regular radiographical examinations were recommended for relapse surveillance. MRD detection was conducted using the MinerVa platform (Genecast Precision Diagnostic Co., Ltd. Wuhan, China) using a tumor-informed strategy based on a fixed next-generation sequencing panel spanning 769 cancer-related genes.

One hundred sixty-five patients were included in this study, with 35 (21.2%) relapses. At landmark, positive MRD was associated with shorter disease-free survival (DFS) than negative MRD (P < .001, hazard ratio, 12.0). MRD was an independent risk factor for shorter DFS, irrespective of the disease stage and high-risk factors. In the case of negative landmark MRD, there was no significant difference between the DFS of (1) those who received AT and those who did not in stage IB patients with high-risk factors (P = .974), (2) epidermal growth factor receptor (EGFR)-mutant patients with or without adjuvant chemotherapy before adjuvant targeted therapy (P = .502), and (3) EGFR/ALK wild-type with or without adjuvant immunotherapy (P = .534). Clearance of ctDNA during AT was associated with a better prognosis than persistently detected ctDNA (P < .001).

ctDNA-based MRD stratifies prognosis after curative resection in NSCLC, with MRD negativity indicating limited benefit from treatment in selected patients and ctDNA clearance reflecting improved outcomes. These findings support the clinical utility of MRD-guided adjuvant treatment strategies.

Clinical genomic profiling of tumors identifies therapeutic targets, while germline pharmacogenomics (PGx) guides drug dosing and toxicity avoidance. However, the combined clinical landscape of both somatic and germline actionable variants across cancers has not been comprehensively defined.

Tumor and matched germline whole-exome sequencing data were analyzed for 10,302 patients in The Cancer Genome Atlas. Somatic mutations with therapeutic relevance were mapped to US Food and Drug Administration (FDA)-approved targeted drugs using the Oncology Knowledge Base database (levels 1-4). Germline PGx variants were identified using PyPGx and cross-referenced with drug-gene interactions in PharmGKB (levels of clinical annotation 1-2). This enabled construction of an integrated germline-somatic PGx profile per patient.

All 10,302 patients (100%) harbored at least one actionable germline PGx variant (median = 3; range = 1-9), including 7,520 (73%) with variants relevant to chemotherapy toxicity or supportive care medications (DPYD, UGT1A1, CYP2C9, and CYP2C19). Somatic profiling revealed 4,312 patients (42%) with at least one actionable mutation matched to an FDA-approved targeted therapy (eg, PIK3CA, KRAS). Across the cohort, 5,275 (51%) patients had more actionable germline variants than somatic mutations, whereas 1,988 (19%) had more actionable somatic mutations.

Integrating germline PGx with somatic profiling reveals that actionable germline variants are nearly universal among patients with cancer in our cohort, extending beyond tumor-specific therapy to encompass toxicity and supportive care management. Routine implementation of combined germline and somatic sequencing in oncology could enhance therapeutic precision, minimize adverse effects, and inform individualized treatment decisions.

Breast cancer (BC) is the most frequent neoplasm. As a consequence of the oncologic treatment, there are diverse adverse effects, as the emotional ones. Treatment options for emotional symptoms like anxiety, depression or stress are limited.

To analyze the effectiveness of psychoeducational workshops among women with BC over the anxiety and depression symptoms.

A randomized clinical trial by blocks with 42 BC patients in stages II and III of the disease, distributed into 2 groups of 21 cases (intervention) and 21 controls. There were 9 psychoeducational workshops performed weekly. It was carried out an initial and final measurement according to the Hospital Anxiety and Depression Scale (HADS).

For the intervention group, the median score for anxiety was 9.09 at the beginning of the study and 5.85 at the end (p = 0.0005). In the control group, the median for anxiety was 8.7 and 6.7 at the end (p = 0.0494). According to the depression symptoms, the median for the intervention group was 5 at the beginning and 3.2 at the end (p = 0.0216). For the control group, the median was 4.7 at the beginning and 4.6 at the end (p = 0.6359).

The psychoeducational workshops demonstrated effectiveness to decrease the symptom burden for anxiety and depression. Early education and counselling for recently diagnosed BC patients should be considered part of the treatment to prevent and decrease these symptoms.

Uncontrolled proliferation is not the only factor driving tumor growth; the tumor microenvironment (TME) has a significant impact. Tissue homeostasis and pathogen removal depend on macrophages, which are important innate immune effector cells. Nevertheless, there is growing evidence that tumor-associated macrophages (TAMs) do not consistently suppress cancer and are functionally diverse. Specifically, M2-polarized TAMs (M2-TAMs) build up in multiple solid tumors, where they promote angiogenesis, metastasis, and immunosuppression, hastening the course of the disease. Here, we critically assess the clinical translatability of TAM-targeted treatment approaches, outline the molecular circuits underpinning M2-TAMs-tumor cell interaction, and extensively explore the phenotypic spectrum and functional diversity of macrophages in cancer. Our objective is to offer a theoretical foundation for upcoming immunotherapeutic interventions.

Oncogenic fusion transcription factors (TFs) frequently drive hematopoietic malignancies by altering gene expression in key developmental programs. TCF3::HLF is a fusion TF that characterizes a rare, treatment-resistant subtype of B cell acute lymphoblastic leukemia [t(17;19) TCF3::HLF-positive B-ALL]. Despite its clinical significance, the mechanisms by which TCF3::HLF induces leukemia are unclear. We used HiChIP mapping and genetic interference to analyze TCF3::HLF at the 3D genome level, revealing enhancer-promoter interactions that control gene activation or repression. Notably, TCF3::HLF directly regulates MEF2C expression through its enhancer, as interference disrupted MEF2C transcription and inhibited leukemia propagation. This disruption also diminished embryonal hematopoietic stem cell (HSC) gene signatures and restored mature HSC and B-lymphoid markers. These findings highlight MEF2C as a critical component of the transcriptional network reprogrammed by TCF3::HLF. Our study provides insight into how TCF3::HLF rewires the 3D genome to drive leukemia and serves as a resource for further exploration of the TCF3::HLF regulome.

Checkpoint inhibitors targeting PD-1 and CTLA-4 have transformed cancer therapy. Both are genetically associated with autoimmune disorders. Moreover, certain immune-related adverse events and autoimmune risk variants are linked to the clinical efficacy of checkpoint inhibition. These associations suggest common principles governing successful cancer immunotherapy and autoimmune susceptibility. Here, we show that ablation of the cytosolic DNA exonuclease TREX1 predisposes mice to autoimmunity while promoting robust antitumor immunity. Constitutive TREX1 loss leads to early onset autoimmunity, characterized by multiorgan CD8+ T cell infiltration, myocarditis, and Sjögren's syndrome-like disease. In contrast, induced systemic TREX1 ablation is well tolerated and promotes effective CD8+ T cell-driven antitumor immunity. Detailed phenotypic studies revealed a notable overlap between productive antitumor and pathogenic autoimmune CD8+ T cell responses. Collectively, we provide mechanistic evidence for interrelated mechanisms underlying autoimmunity and successful cancer immunotherapy, uncover key parallels between adaptive T cell and innate immune checkpoints, and suggest that targeting autoimmune risk genes represents a promising future avenue for cancer immunotherapy.

T cell exhaustion is a major barrier to effective antitumor immunity, yet the tumor-intrinsic mechanisms remain poorly defined. Through single-cell and spatial proteomics analyses of esophageal squamous cell carcinoma (ESCC), we uncover two infection-like CD8⁺ T cell trajectories, acute-like and chronic-like responses, whose fates are dictated by the tumor cell subtypes they encounter. This concept links tumor heterogeneity to the shaping of local immune niches. Mechanistically, we identify CDC28 protein kinase regulatory subunit 1B (CKS1B) as a tumor-intrinsic inducer of chronic-like exhaustion. CKS1B forms a complex with S-phase kinase-associated protein to promote interferon regulatory factor 3 (IRF3) ubiquitination and degradation, thereby suppressing type I interferon signaling and antigen presentation. This impairs tumor cell elimination and drives progressive CD8⁺ T cell stimulation and exhaustion. Pharmacological blockade of the CKS1B-IRF3 interaction with 14i restores CD8⁺ T cell function and synergizes with immune checkpoint blockade. The tumor-intrinsic oncogenic-immune axis, which connects cancer cell signaling to immune dysfunction, is conserved across multiple malignancies, establishing a conceptual and therapeutic framework for overcoming tumor-driven T cell exhaustion.

Breast cancer is the leading cause of cancer mortality among women globally, and drug resistance complicates treatment. Garlic-derived organosulfur compounds exhibit anticancer potential, but their multi-target activity against key breast cancer biomarkers remains unclear. This study utilized AutoDock Vina for molecular docking, OpenBabel for post-docking energy minimization, and employs SWISS-ADME and PreADMET platforms for ADMET profiling to assess six garlic compounds (Z-ajoene, allyl-methyl trisulfide, diallyl disulfide, diallyl sulfide, diallyl trisulfide, and S-allyl-L-cysteine) against clinically relevant breast cancer targets. Z-ajoene showed strong binding to Bcl-2, Topoisomerase II, and CDK-2, while S-allyl-L-cysteine targets five biomarkers. All compounds complied with Lipinski's rule of five, indicating good oral bioavailability, and display favorable ADMET properties with no mutagenic or tumorigenic risks. Most compounds were predicted to inhibit P-glycoprotein, while only Z-ajoene showed potential inhibition of CYP2C9, suggesting possible drug-drug interactions. Despite moderate affinities, these compounds may serve as potential promising multi-target agents in breast cancer therapy. Our computational findings provide preliminary evidence that garlic-derived compounds warrant further in vitro and in vivo evaluation, particularly in the context of drug-resistant breast cancer.