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.

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.

Radiotherapy has long been first-line treatment for brain metastases. However, CNS penetrating systemic therapies are increasingly used as first-line alternatives. There is little evidence guiding surveillance in this setting. Here we retrospectively assessed surveillance strategies at a single institution and associated outcomes.

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.

The majority of breast cancer-related deaths result from metastatic progression, especially brain metastasis, associated with the poorest prognosis. Patients with triple-negative breast cancer (TNBC) are particularly prone to developing brain metastases. In this context, the blood-brain barrier (BBB) plays a pivotal role; however, the contribution of brain pericytes in mediating interactions between TNBC cells and the brain endothelial cells (ECs) remains unclear. To investigate the role of pericytes in modulating these interactions, we used a syngeneic human in vitro BBB model, composed of human brain-like endothelial cells (hBLECs) co-cultured with human brain pericytes (hBPs). Our findings demonstrate that hBPs secretions significantly reduce TNBC cell adhesion to hBLECs and protect the endothelium from TNBC cell-induced damage, both under normoxic and hypoxic conditions. Interestingly, we found that hBPs promote TNBC cell migration, invasion, and increase clonogenicity. Together, these findings uncover a dual role of brain pericytes in TNBC brain metastasis: they protect ECs and maintain BBB integrity against TNBC cells while simultaneously promoting tumor aggressiveness. Understanding this balance between protective and pro-metastatic functions may provide insights for developing novel therapeutic approaches to strengthen BBB defenses and limit brain colonization in TNBC patients.