Background and aim Splenic metastases are uncommon and typically occur in advanced malignancies despite the spleen's extensive vascular network. This retrospective, single-center cohort study aimed to provide an incidence-based evaluation of splenic metastases in a large PET/CT population and to assess their prognostic implications in contemporary clinical practice. Materials and methods Between January 2018 and December 2024, 41 cases (0.40%) of splenic metastases were identified among 10,295 patients with nonhematologic malignancies undergoing fluorodeoxyglucose (FDG) PET/CT. Metastases were verified through histopathology or, more commonly, through imaging-based criteria supported by longitudinal clinical and radiological follow-up, with consensus evaluation by two experienced nuclear medicine physicians. Maximum standardized uptake value (SUVmax) measurements were obtained for all splenic lesions. Results The mean SUVmax was 8.39 ± 4.03 (range: 3.89-22.22). The most common primary tumors were lung (34.15%), ovarian (21.95%), breast (9.76%), and colorectal (9.76%) cancers. All cases demonstrated concomitant metastatic involvement in other organs, with no isolated splenic metastases observed. Median overall survival was 7.1 months, with one-year and two-year survival rates of 31.7% and 28.2%, respectively. Patients with lung cancer showed significantly poorer overall survival compared to other primary tumors (HR = 2.43, 95% CI: 1.15-5.16, p = 0.020). In multivariate analysis, age and male sex were independently associated with overall survival. Conclusions Splenic metastases are rare (0.40%) in nonhematologic malignancies and are typically associated with widespread metastatic disease. The most common primary tumors are lung, ovarian, breast, and colorectal cancers. Survival is poor following splenic metastasis detection, with a median overall survival of 7.1 months. These findings provide valuable epidemiologic and prognostic data on splenic metastases detected by FDG PET/CT in clinical practice.

Lung cancer remains a leading cause of global cancer-related mortality, with most patients diagnosed at advanced stages. The emergence of immune checkpoint inhibitors (ICIs), specifically targeting PD-1/PD-L1 and CTLA-4 pathways, has revolutionized the treatment landscape by restoring anti-tumor immune responses. Currently, ICIs are integrated into clinical practice across all stages of lung cancer, administered either as monotherapy or in combination with chemotherapy, radiotherapy, and anti-angiogenic agents. Despite significant survival benefits, several critical challenges persist. First, primary and acquired resistance, driven by tumor microenvironment (TME) immunosuppression, impaired antigen presentation, and aberrant signaling, limits long-term efficacy. Second, existing biomarkers like PD-L1 expression and tumor mutational burden (TMB) face limitations due to insufficient standardization and spatiotemporal heterogeneity. Furthermore, immune-related adverse events (irAEs) across multiple organ systems necessitate vigilant clinical management and occasionally treatment discontinuation. This review systematically evaluates the research progress and clinical applications of ICI therapy in lung cancer. We highlight the therapeutic heterogeneity observed across different histological types, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with a specific focus on the management of brain metastases (BMs). Additionally, the article discusses varying response patterns within specific patient subgroups, such as geriatric patients and individuals with differing smoking or performance statuses. By synthesizing data on both favorable therapeutic outcomes and the spectrum of irAEs, we emphasize the necessity of personalized immunotherapy. Ultimately, this review looks forward to future advancements aimed at enhancing the precision and safety of lung cancer treatment, providing a roadmap for more tailored clinical interventions.

During metastasis, circulating tumor cells (CTCs) are subjected to fluidic shear stress (SS), which eliminates many of them but paradoxically enhances malignancy and metastatic success. Meanwhile, given the critical roles of reactive oxygen species (ROS) in stress response and cancer, we engineer a circulation-mimicking microfluidic system which generates pulsatile SS to investigate the interplay among SS, ROS and metastasis. A 3-hour SS treatment rapidly elevates ROS levels, boosting metastatic abilities in triple-negative breast cancer (TNBC) cells in vitro and in vivo. RNA-sequencing and subsequent investigation identify activator protein-1 (AP-1) transcription factor members FOS, ATF3 and FOSB, which undergo dramatic ROS-dependent increase and nuclear localization upon SS stimulation. All three genes exhibit metastasis-promoting potential, while FOS displays the strongest ability to trigger distant lung metastasis in an orthotopic tumor model and correlates with worse clinical outcomes. Mechanistically, calcium channel acts as the mechano-sensor to initiate the SS-ROS cascade, with calcium channel blockers Mibefradil and Nifedipine effectively weakening SS-ROS-induced invasiveness. Following ROS elevation, the downstream activation of p38-ELK1-cFOS and JNK-cJUN pathways subsequently increase the expression of malignancy-related genes. This metastasis-promoting SS-calcium channel-ROS-FOS axis provides new insights for combating metastatic progression in breast cancer.

Leptomeningeal metastatic disease (LMD) is associated with a poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who experience disease progression after EGFR tyrosine kinase inhibitor therapy. Amivantamab, an EGFR-mesenchymal-epithelial transition bispecific antibody, has demonstrated clinical efficacy in EGFR-mutated NSCLC; however, its effectiveness in treating symptomatic brain metastases and LMD remains unclear. We report on two cases of LMD that were managed with amivantamab. In Case 1, a 44-year-old woman developed symptomatic LMD during osimertinib therapy. Owing to prior prophylactic whole-brain irradiation during childhood, additional radiotherapy was not feasible. Carboplatin, pemetrexed, and amivantamab treatment resulted in remarkable LMD radiological improvement and gradual neurological symptom resolution. In Case 2, a 69-year-old man developed multiple asymptomatic brain metastases and LMD during osimertinib therapy. Second-line treatment with carboplatin, pemetrexed, and amivantamab resulted in a radiological response. To our knowledge, this is the first report to demonstrate the efficacy of carboplatin, pemetrexed, and amivantamab against LMD progression after osimertinib therapy, suggesting that this regimen may be a therapeutic option for patients with LMD, including those with symptomatic disease. Nevertheless, further studies are warranted to confirm efficacy in this population.

Emerging evidence suggests that GRIP and coiled-coil domain-containing two enriched small extracellular vesicles (sEV-GCC2) may serve as diagnostic biomarkers of early-stage lung adenocarcinomas. However, the roles of these molecules remain unclear. This study evaluated the diagnostic and prognostic potential of sEV-GCC2 for detecting early-stage lung adenocarcinoma and its tumourigenic role in vitro and in vivo. This retrospective multicentre study analyzed 470 plasma samples (320 lung adenocarcinoma patients, 150 controls; mean follow-up: 34.7 ± 24.0 months) across five institutions. Size-exclusion chromatography and enzyme-linked immunosorbent assay were used to measure sEV-GCC2 levels, whereas immunohistochemistry was used to confirm GCC2 expression in tumour tissues. Functional studies were performed using the PC9 and H1650 lung adenocarcinoma cell lines in vitro and the corresponding PC9-based preclinical models in vivo to evaluate the tumour-related effects of sEV-GCC2. Patients exhibited significantly elevated sEV-GCC2 levels compared to controls (area under the receiver operating characteristic (ROC) curve [AUC]: 0.904, P < 0.001), with similar results in stage TisN0-T1miN0 disease (AUC: 0.781, P < 0.001). sEV-GCC2 levels were associated with the pathological TNM stage and tumour location. Higher sEV-GCC2 levels were correlated with poorer recurrence-free survival (RFS), overall survival and recurrence rates, even in patients with stage 0-IA1 disease. Functional studies have revealed that sEV-GCC2, but not GCC2-deficient sEVs, promote cancer cell proliferation, tumour growth and lymph node metastasis in vitro and in vivo. These findings highlight the diagnostic and prognostic potential of sEV-GCC2 and its tumourigenic role in early-stage lung adenocarcinoma. This study was registered at ClinicalTrials.gov (NCT04529915).

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival and is largely refractory to standard therapies. Most patients present with locally advanced or metastatic disease, and those with early-stage tumors amenable to surgical resection face high rates of metastatic relapse. Despite the many successes of immunotherapy in other solid tumors, these approaches have shown only marginal activity in PDAC. In PDAC, metastasis occurs through a coordinated, multistep process characterized by a gradient loss of immune surveillance. This process begins with establishment of a receptive premetastatic niche, which occurs via conditioning of distant tissues by tumor-derived exosomes and the recruitment of myeloid cells, leading to extracellular matrix remodeling and local immunosuppression prior to metastatic dissemination. On arrival of metastatic cells, tissues undergo organ-specific immune editing with important implications for therapeutic vulnerability. Importantly, liver metastases maintain a profoundly immunosuppressive environment whereas lung metastases have higher immune activity. These observations challenge the prevailing assumption that insights from primary tumors are broadly applicable to metastatic disease, establishing metastatic PDAC as a distinct immunologic entity. This framework identifies unique therapeutic opportunities across the disease spectrum from early interventions targeting premetastatic niche formation to site-specific strategies for established metastatic disease.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) significantly contribute to poor prognosis, with their progression intrinsically linked to the unique immune microenvironment of the brain. This review comprehensively examines the dual regulatory roles and underlying mechanisms of three pivotal cell types within the metastatic niche-tumor-associated macrophages (TAMs), microglia, and astrocytes-during brain metastasis development. TAMs promote tumor invasion and the establishment of an immunosuppressive milieu through metabolic regulation and differentiation into functional subtypes, with profiles distinct from those in primary tumors. As resident immune cells of the central nervous system, microglia show marked functional polarization: they can inhibit metastasis by directly targeting tumor cells, cooperating with adaptive immunity, and enhancing radiosensitivity. However, under specific microenvironmental cues, they may also support tumor growth and immune evasion. Similarly, astrocytes transition from a neuroprotective to a tumor-promoting phenotype, driving progression through inflammatory cytokine secretion, gap junction-mediated intercellular communication, metabolic reprogramming, and exosomal signaling. Building on these mechanistic insights, this review further summarizes emerging therapeutic strategies targeting these cell types, including engineered vesicle-mediated TAM reprogramming, nanoparticle-based combination therapies, metabolic checkpoint interventions, and targeted signaling pathway inhibitors. These insights advance the "seed and soil" hypothesis in brain metastasis and support the development of precision therapies targeting the microenvironment to improve outcomes for patients with NSCLC and BM.