Iliescu, Cezar

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation. Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension. Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined. Future Directions: Mitochondrial and cytosolic ROS sources—arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity—shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000–000.

Poor diet is the leading preventable risk factor for death worldwide, associated with over 10 million premature deaths and USD 8 trillion related costs every year. Artificial intelligence or AI is rapidly emerging as the most historically disruptive, innovatively dynamic, rapidly scaled, cost-efficient, and economically productive technology (which is increasingly providing transformative countermeasures to these negative health trends, especially in low- and middle-income countries (LMICs) and underserved communities which bear the greatest burden from them). Yet widespread confusion persists among healthcare systems and policymakers on how to best identify, integrate, and evolve the safe, trusted, effective, affordable, and equitable AI solutions that are right for their communities, especially in public health nutrition. We therefore provide here the first known global, comprehensive, and actionable narrative review of the state of the art of AI-accelerated nutrition assessment and healthy eating for healthcare systems, generated by the first automated end-to-end empirical index for responsible health AI readiness and maturity: the Responsible Health AI readiness and Maturity Index (RHAMI). The index is built and the analysis and review conducted by a multi-national team spanning the Global North and South, consisting of front-line clinicians, ethicists, engineers, executives, administrators, public health practitioners, and policymakers. RHAMI analysis identified the top-performing healthcare systems and their nutrition AI, along with leading use cases including multimodal edge AI nutrition assessments as ambient intelligence, the strategic scaling of practical embedded precision nutrition platforms, and sovereign swarm agentic AI social networks for sustainable healthy diets. This index-based review is meant to facilitate standardized, continuous, automated, and real-time multi-disciplinary and multi-dimensional strategic planning, implementation, and optimization of AI capabilities and functionalities worldwide, aligned with healthcare systems’ strategic objectives, practical constraints, and local cultural values. The ultimate strategic objectives of the RHAMI’s application for AI-accelerated public health nutrition are to improve population health, financial efficiency, and societal equity through the global cooperation of the public and private sectors stretching across the Global North and South.