Casso-Chapa, Bernardo

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.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.