Lung cancer remains the leading cause of cancer-related mortality worldwide. Since 2024, the non–small-cell lung cancer (NSCLC) landscape has undergone a transformative shift, driven by 11 FDA approvals. Recent advances in molecular profiling, targeted therapies, and immunotherapies have revolutionized NSCLC management, ushering in an era of personalized treatment with improved patient outcomes. The increased adoption of low-dose computed tomography (LDCT) for screening has enhanced early detection, enabling intervention at more curable stages. Molecular diagnostics now play a pivotal role in guiding treatment strategies, with actionable genomic alterations (AGAs) informing the use of EGFR, ALK, ROS1, KRAS, NRG1, and other targeted inhibitors in both early and advanced settings. For instance, targeted therapies are increasingly being integrated into early-stage management, with adjuvant osimertinib for EGFR -mutated NSCLC and alectinib for ALK -positive NSCLC demonstrating substantial survival benefits. Immunotherapy, particularly immune checkpoint inhibitors, has become a cornerstone of treatment for AGA-negative NSCLC, either as monotherapy or in combination with chemotherapy, and is increasingly being utilized in the perioperative setting. Furthermore, emerging therapies such as bispecific antibodies, antibody–drug conjugates (ADCs), and novel immunotherapeutic agents show promise in addressing resistance mechanisms and improving outcomes in advanced-stage disease. Although new challenges arise, the evolving NSCLC treatment paradigm continues to prioritize precision medicine, offering hope for prolonged survival and enhanced quality of life for patients.

Lung cancer is a leading cause of brain metastases (BMs), with 10–20% of patients with non-small cell lung cancer (NSCLC) presenting with BMs at diagnosis and 25–50% developing them over the course of their disease. Historically, BMs have posed significant therapeutic challenges, partly due to the blood brain barrier (BBB), which restricts drug penetration to the central nervous system. Consequently, BMs were initially managed with local treatments, including surgical resection, stereotactic radiosurgery, and whole brain radiation therapy. In recent years, however, systemic treatments for BMs have advanced significantly, particularly with the development of molecularly-targeted therapies and immunotherapies. The discovery of driver mutations and the development of novel tyrosine kinase inhibitors (TKIs) have yielded encouraging intracranial responses in NSCLC patients with actionable genetic alterations (e.g., EGFR, ALK, ROS1). Genomic profiling has also suggested genetic heterogeneity between BMs and primary sites. Immunotherapies, alone or in combination with other treatments, have demonstrated promising results in NSCLC with BMs, although most clinical trials have included only selected patients with asymptomatic or previously treated BMs. In this review, we discuss the molecular and immune characteristics of NSCLC with BMs, analyze intracranial efficacy findings from clinical trials, and explore treatment strategies for lung cancer patients with BMs.

Brain metastases (BMs) are a relatively common and severe complication in advanced non-small cell lung cancer (NSCLC), significantly affecting patient prognosis. Metastatic tumor cells can alter the brain tumor microenvironment (TME) to promote an immunosuppressive state, characterized by reduced infiltration of tumor-infiltrating lymphocytes (TILs), diminished expression of programmed death-ligand 1 (PD-L1), and changes in other proinflammatory factors and immune cell populations. Microglia, the resident macrophages of the brain, play a pivotal role in modulating the central nervous system (CNS) microenvironment through interactions with metastatic cancer cells, astrocytes, and infiltrating T cells. The M2 phenotype of microglia contributes to immunosuppression in BM via the activation of signaling pathways such as STAT3 and PI3K-AKT-mTOR. Recent advances have enhanced our understanding of the immune landscape of BMs in NSCLC, particularly regarding immune evasion within the CNS. Current immunotherapeutic strategies, including immune checkpoint inhibitors, have shown promise for NSCLC patients with BM, demonstrating intracranial activity and manageable safety profiles. Future research is warranted to further explore the molecular and immune mechanisms underlying BM, aiming to develop more effective treatments.

Background: People living with HIV (PWH) are underrepresented in immune checkpoint inhibitor (ICI) and targeted therapy trials, despite a growing burden of malignancies. Cabozantinib may remodel the tumor microenvironment by reducing immunosuppressive myeloid populations and enhancing cytotoxic T-cell infiltration, thereby augmenting antitumor immunity and providing a biologic rationale for combination with programmed cell death protein 1 (PD-1) blockade. However, prospective data on combined ICI and antiangiogenic strategies in PWH are limited. Methods: We conducted a multicenter pilot trial of cabozantinib plus nivolumab in PWH with advanced solid tumors receiving stable antiretroviral therapy. The primary endpoints were safety and feasibility. Secondary endpoints included disease control and longitudinal HIV parameters. To place the trial findings in context, we also conducted a focused systematic review of prospective studies evaluating ICIs and relevant targeted therapies in PWH with cancer. Results: Between November 2021 and January 2024, 8 participants were enrolled and 7 initiated treatment (Kaposi sarcoma, n = 5; chondrosarcoma, n = 1; prostate cancer, n = 1). No dose-limiting toxicities occurred. Grade 3 treatment-related adverse events were infrequent; no grade 4 or 5 treatment-related adverse events occurred. Among 6 response-evaluable participants, best overall response was stable disease in 5, including disease stabilization lasting >12 months in 3 heavily pretreated participants. HIV viral load and CD4 counts remained stable during treatment. The literature review supported the feasibility of immune checkpoint inhibition in selected PWH receiving antiretroviral therapy, with the strongest prospective activity signal in Kaposi sarcoma. Conclusion: Nivolumab plus cabozantinib had a manageable safety profile without an apparent loss of HIV virologic control in available measurements. Durable disease stabilization occurred in some participants, but antitumor efficacy cannot be determined from this small, heterogeneous cohort. These findings support larger dedicated studies in PWH, particularly in Kaposi sarcoma. Clinical trial registration: ClinicalTrials.gov identifier NCT04514484.