Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60–70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.

INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive white matter (WM) degeneration. Circulating lipid metabolites may serve as early indicators of WM microstructural changes. In this study, we investigated the associations between plasma lipid metabolites and WM integrity across the cognitive continuum. METHODS: We included 173 participants from the Alzheimer's Disease Neuroimaging Initiative (51 cognitively normal [CN], 88 mild cognitive impairment [MCI], 34 AD) database. Plasma metabolites were quantified using targeted lipidomics, and diffusion tensor imaging (DTI) metrics were derived from 52 predefined WM regions. RESULTS: Regression analyses revealed widespread metabolite–DTI associations in MCI, particularly within the corpus callosum. The callosal body and splenium showed significant inverse associations with phosphatidylcholines (PCs) and multiple lysophosphatidylcholines (lysoPCs) species. In AD group, inverse relationships between PCs and the internal capsule were observed. DISCUSSION: Circulating lipid metabolites are linked to WM microstructure in both prodromal and clinical AD, supporting their potential as sensitive biomarkers of early vulnerability and disease progression. Highlights: Circulating lipid metabolites link to white matter integrity in early Alzheimer's disease (AD) Phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), and propionylcarnitine associate with tract‐specific diffusion magnetic resonance imaging (dMRI) metrics No metabolite–white matter associations detected in established AD Plasma metabolites may serve as biomarkers of early white matter degeneration

The glymphatic system plays a critical role in clearing metabolic waste and neurotoxic proteins from the brain, and its dysfunction is implicated in neurodegenerative diseases such as Alzheimer’s disease (AD). Emerging evidence indicates that physical exercise enhances glymphatic function through multiple mechanisms, including increased cerebrospinal fluid (CSF) influx, improved perivascular clearance, astrocytic aquaporin-4 (AQP4) polarization, and modulation of vascular and sleep-dependent processes. Preclinical studies demonstrated that voluntary wheel running and aerobic exercise reduce amyloid-β (Aβ) accumulation, attenuate neuroinflammation, and improve cognitive performance in both aging and AD mouse models, with benefits being highly dependent on AQP4 expression and the timing of intervention. Translational evidence in humans showed that structured aerobic and multicomponent exercise increases glymphatic and meningeal lymphatic activity, enhances vascular dynamics, reduces systemic inflammation, and improves sleep quality, leading to measurable cognitive gains. Despite these promising findings, methodological challenges—such as limitations of non-invasive imaging, difficulty establishing causality, and reliance on short-term interventions—highlight the need for longitudinal, multimodal studies that integrate imaging, cardiovascular, sleep, and cognitive metrics. Collectively, these data suggest that exercise represents a potent non-pharmacological strategy to augment glymphatic clearance, preserve neural homeostasis, and reduce the risk of cognitive decline. This review will summarize evidence on exercise-induced glymphatic enhancement, highlight mechanisms, and identify research gaps for future studies on brain health.

Early diagnosis of Alzheimer’s disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ_1–42 ratio, NfL, and GFAP, and greater MTL atrophy. Higher plasma p-tau217 and p-tau217/Aβ_1–42 were associated with reduced bilateral hippocampal and CA1 volumes in MCI (β = − 0.37 to − 0.28; FDR p < 0.02). In CN, these biomarkers were positively associated with left hippocampal volume (β ≈ 0.19; FDR p = 0.04), and GFAP correlated with larger sulcal volume (FDR p = 0.03). Mediation analysis demonstrated that in CN individuals, the relationship between p-tau217/Aβ_1–42 and left sulcal volume was partially mediated by GFAP (indirect β = 0.11; FDR p = 0.048). This study reveals stage-specific plasma biomarker–MTL relationships across the Alzheimer’s continuum. In MCI, plasma p-tau217 and its ratio to Aβ_1–42 closely track hippocampal subfield atrophy, reflecting tau-related neurodegeneration. In CN individuals, higher p-tau217 and p-tau217/Aβ_1–42 levels relate positively to hippocampal integrity, partly mediated by GFAP, suggesting early astroglial activity preceding structural loss. These findings underscore dynamic biomarker interactions and support integrating plasma and imaging markers for early AD characterization.