SHP2: A Redox-Sensitive Protein Connecting Immune Checkpoint Therapy with Cancer Treatment and Blood Vessel Risk

Phosphatase enzyme activation depends on SHP2, which exists in a fragile balance between an open active conformation and an autoinhibited basal state [12]. The N-SH2 domain in the basal state limits access to the catalytic site contained in the PTP domain, therefore preventing substrate from engaging the PTP catalytic site. When SHP2 is stimulated with growth factors (e.g., EGF) or other cytokines, the phosphotyrosine residues of the bound molecules will bind to the N-SH2 domain, and surface interactions and conformations will induce release of this autoinhibition to expose the catalytic site and activate the SHP2 phosphatase activity [8,13] (Figure 1B). Also, the unique C-terminal tail of SHP2 is a significant regulatory region for SHP2 activity. As an example, the phosphorylation of Y542 would disrupt the N-SH2 domain's interaction with the PTP domain, allowing an active conformation of SHP2 to occur. Interestingly, Y580 phosphorylation improved SHP2 catalytic efficiency by enhancing the engagement of the C-SH2 domain of SHP2 [9,13,14] (Figure 1B).

As a phosphatase, SHP2 is a fundamental component for intracellular signaling as it negatively directs the phosphorylation state of important adaptor proteins that contribute to signaling. Among the way phosphatases are classically defined as negative regulators of signaling, SHP2 is unique; SHP2 can activate signaling pathways with dephosphorylation by promoting the complex with proteins necessary to signal. The functional role of SHP2 in this regard is particularly important as it is a positive regulator of receptor tyrosine kinase (RTK) signaling, as well as the Ras/mitogen-activated protein kinase (MAPK) pathway [13]. In this role, SHP2 actively works on specific phosphotyrosine residues of the various adaptor proteins, including the single insulin receptor substrate protein, IRS1, and Grb2 associated binder 1 (GAB1) (Figure 1B and Figure 2). Both IRS1 and GAB1 have over-phosphorylated states that can sequester or recruit inhibitory proteins. By either dephosphorylating inhibitory phosphotyrosines or dephosphorylating non-productive phosphotyrosines, SHP2 promotes conformational changes or exposure of new docking sites for recruiting the GRB2/SOS protein complex to the plasma membrane [8]. GRB2/SOS is crucial for Ras proteins that are inactivated because SOS catalyzes the exchange of GDP for GTP on Ras, converting Ras to the active GTP-bound Ras. Activated Ras initiates a downstream kinase cascade (RAF → MEK → ERK), ultimately activating the transcription of the target genes responsible for proliferation, survival, and motility [8] (Figure 2A).

It has been reported that tyrosine-phosphorylated substrates can engage not only the SH2 domains of SHP2 but also its catalytic PTP domain (Figure 2B). Structural studies have demonstrated that the SHP2 PTP domain can directly bind phosphopeptides derived from IRS1 and CD28, extending beyond the classical SH2–phosphotyrosine docking mechanism [15]. Recent crystal structures further revealed that the PTP active site accommodates the phosphorylated tyrosine while simultaneously sensing adjacent Ser/Thr phosphorylation, which stabilizes substrate binding and modulates catalytic efficiency. This represents a form of substrate-assisted regulation, emphasizing that SHP2 substrate specificity and activity are shaped by the broader sequence context of its binding partners, rather than solely by SH2 domain recruitment [15]. Functionally, this dual mode of substrate recognition allows SHP2 to fine-tune signaling in diverse biological contexts. In insulin signaling, SHP2 binding and dephosphorylation of IRS1 help regulate the PI3K–AKT pathway, preventing excessive activation and maintaining balanced metabolic responses [16] (Figure 2B). In T cell activation, SHP2 interaction with phosphorylated CD28 modulates co-stimulatory signaling, acting as a checkpoint that defines activation thresholds as also described later [17,18] (Figure 2B). Collectively, these findings establish SHP2 as a critical signal integrator that is recruited through SH2 docking but exerts additional regulatory control through direct PTP–substrate interactions, and thus, shapes pathways essential to metabolism, immunity, and disease.

SHP2 is a further example of a positive modulator of AMP-activated protein kinase (AMPK), particularly in relationship to metabolic challenge (Figure 3). While SHP2 is typically discussed in the chemotherapy context of mitogenic signaling, it can also help with energy homeostasis via facilitating AMPK activation. The phosphatase activity of SHP2 decreases the inhibitory phosphorylation of AMPK-mTOR axis components, which initiates AMPK activation [19]. The overall outcome of AMPK activation is the inhibition of mTORC1 activity and stimulation of autophagy (particularly through ULK1 phosphorylation) [20]. For example, in pulmonary fibroblasts, SHP2 has been shown to mediate AMPK activation as a means to promote mitophagy and metabolic reprogramming during mitochondrial stress [19]. In a neural context, SHP2 acts as a positive upstream modulator of AMPK, a master regulator of cellular energy homeostasis. Functionally, SHP2 promotes AMPK activation under energy-deprived conditions, allowing AMPK to inhibit anabolic processes and maintain energy balance. AMPK, in turn, suppresses the mTOR/S6K1 (S6 kinase 1) pathway—a key driver of protein synthesis and cell growth—by phosphorylating upstream regulators like TSC2 and Raptor. Loss of SHP2 results in impaired AMPK signaling, leading to unchecked S6K1 activity and dysregulation of cellular growth responses [21,22]. While SHP2 is best known for its canonical pathways of signaling, the information presented above demonstrates that SHP2 functions as a metabolic integrator in animal cells to link energy sensing to adaptive cellular responses.

SHP2 is a positive modulator of AMP-activated protein kinase (AMPK), particularly under metabolic stress (Figure 3). Although commonly associated with mitogenic signaling in chemotherapy contexts, SHP2 also supports energy homeostasis by facilitating AMPK activation. Its phosphatase activity reduces inhibitory phosphorylation within the AMPK–mTOR axis, triggering AMPK activation [19]. Activated AMPK suppresses mTORC1 and promotes autophagy, notably through ULK1 phosphorylation [20]. In pulmonary fibroblasts, SHP2-mediated AMPK activation enhances mitophagy and metabolic reprogramming during mitochondrial stress [19]. Similarly, in neurons, SHP2 acts upstream of AMPK to maintain energy balance under nutrient deprivation by inhibiting anabolic pathways. AMPK then downregulates the mTOR/S6K1 pathway via phosphorylation of TSC2 and Raptor. Loss of SHP2 impairs AMPK signaling, leading to unchecked S6K1 activity and dysregulated growth responses [21,22]. These findings highlight SHP2 as a metabolic integrator linking energy sensing to adaptive cellular responses.

While SHP2 activates mitogenic pathways such as Ras/MAPK, it can negatively regulate JAK/STAT signaling (Figure 4). This occurs mainly through its phosphatase activity, which dephosphorylates STAT1, STAT3, and STAT5 after cytokine stimulation, preventing dimerization, nuclear translocation, and gene activation. In immune cells, this mechanism helps maintain homeostasis and limit inflammation. SHP2 deficiency prolongs STAT1 phosphorylation, increasing IFN-γ sensitivity and immune activation [23]. Conversely, SHP2 overexpression inhibits IL-3-induced STAT5 activation, reducing hematopoietic cell proliferation [24]. In prostate cancer, SHP2 downregulates STAT1, as its loss enhances STAT1 phosphorylation and immune marker expression (HLA-ABC, PD-L1) [25]. SHP2 also modulates IL-6 signaling by restraining excessive STAT3 activation while preserving pathway integrity [26]. Overall, SHP2 acts as a phosphatase that constrains JAK/STAT signaling, balancing immune responses and maintaining signaling fidelity across contexts.

Thus, SHP2 enhances signaling by changing the phosphorylation landscape to allow productive protein–protein interactions and downstream activation as opposed to inhibiting signaling. SHP2 can use dephosphorylation in a context-dependent manner, suggesting that SHP2 acts as a signal amplifier and not a signal terminator [13]. The precise and regulated activation of SHP2 is more pertinent in the context of the associated mutations in the PTPN11 gene of SHP2. PTPN11 gain-of-function mutations (e.g., Noonan syndrome) ablate the autoinhibited binding of the N-SH2 (N-terminal SH2) domain on the PTP, actively creating a situation where SHP2 is constitutively activated with complete freedom from having to rely on upstream signals. This aberrant activation is likely to "amplify Ras/MAPK signaling" and promote the various developmental features observed in patients with Noonan syndrome [27] (Figure 3). Mutations causing LEOPARD Syndrome work based on variations on the mutation and may often be catalytically impaired in the normal process but still allow for pathological SHP2 activation by destabilizing the inactivity conformation, alter binding specificity on the two possible SH2 domains, and enable greater opportunities to engage with signaling partners [28,29]. These studies are not only enlightening for determining SHP2 activity but also raise important points about the conformation and mechanisms of protein–protein interactions of SHP2 and regulation of intracellular signaling. These contexts also provide an important distinction of context-dependent effects; in some instances, these mutations obstruct phosphatase activity, while allowing for signaling through the mutation, causing a prominence of conformation or adapter roles [29].

SHP2 regulates PI3K/AKT signaling in a context-dependent manner through interacting with p85, the PI3K regulatory subunit (Figure 3). In growth factor signaling (e.g., EGF, IGF) and pharmacologic models, SHP2 acts as a positive regulator by promoting PI3K activation and subsequent AKT phosphorylation. This facilitation requires the N-terminal SH2 domain to bind p85 [30] (Figure 3). In oncogenic v-Src signaling, SHP2 is essential for AKT activation and survival signaling [31] (Figure 3). Conversely, in ovarian granulosa cells under oxidative stress (e.g., H₂O₂), SHP2 binds p85 but suppresses AKT phosphorylation, acting as a negative regulator [32] (Figure 4). These findings indicate that SHP2's role in PI3K/AKT signaling varies by stimulus, cell type, and disease context, reflecting its dynamic function in cellular networks.

The recent discovery of SHP2 in mitochondria has enhanced our understanding of SHP2 cellular function, specifically with respect to mitochondrial function and energy metabolism. SHP2 was first identified as a tyrosine phosphatase in the mitochondria and has contributed greatly to mitochondrial bioenergetics [33,34]. For instance, gain-of-function mutations in the PTPN11 gene, E76K and D61G, increased the activity of the mitochondria complexes I and III electron transport chain, increased mitochondrial membrane potential, and increased reactive oxygen species (mtROS) production; all findings are indicative of high oxidative stress and metabolic activity. These examples, along with many others, highlight the important contribution of SHP2 to the delicate balance of energy production and redox homeostasis of the mitochondria [33] (Figure 5).

SHP2 has also been implicated in the regulation of innate immunity in regard to mitochondrion-derived immune responses. Importantly, SHP2 does not solely promote mtROS production; it can also act to suppress excessive ROS generation under certain conditions. One such mechanism involves the regulation of adenine nucleotide translocase 1 (ANT1), where SHP2-mediated dephosphorylation helps maintain mitochondrial membrane potential and prevents the release of mitoROS and mitochondrial DNA. Upon the activation of the NLRP3 inflammasome, it has been shown that SHP2 schedules translocation to the mitochondria to dephosphorylate ANT1, a protein that is part of the mitochondrial permeability transition pore (mPTP), which prevents loss of mitochondrial membrane potential, and thus prevents loss of mitochondrial DNA and ROS, which are both critical for the activation of the NLRP3 pathway. Therefore, dephosphorylation of ANT1 represents a key strategy for managing NLRP3 hyper-activation to limit overactive mtROS and inflammatory responses. These findings suggest that there is a potential for SHP2 to modulate mitochondria functions and thereby mitochondrion-derived immune signaling to regulate specific cellular stress responses to preserve mitochondrial integrity and limit inflammation damage [35] (Figure 5).

SHP2 is a central player in mitochondrial function, cellular metabolism, and inflammation—three interrelated pathways that directly influence cellular senescence. However, the role of mitochondrial SHP2 in regulating mtROS is context-dependent, as described above. While overactive SHP2 in mitochondria has been associated with increased mtROS production—leading to DNA damage, disruption of metabolic homeostasis, and activation of ERK1/2 signaling—SHP2 can also act to suppress excessive ROS generation under certain conditions, such as through the dephosphorylation of ANT1 to preserve mitochondrial membrane potential. These divergent effects highlight SHP2's role in maintaining redox balance rather than simply promoting oxidative stress. When mitoROS levels are elevated, they can trigger the senescence-associated secretory phenotype (SASP), characterized by the expression and secretion of pro-inflammatory cytokines and matrix-degrading enzymes [36,37]. Thus, mitochondrial SHP2 may either inhibit or promote senescence depending on the cellular environment and upstream signals (Figure 5).

This dual role of SHP2 contrasts with its well-established anti-inflammatory functions in immune cells. In T cells and macrophages, SHP2 acts downstream of PD-1 signaling to promote immune tolerance by dampening T cell receptor signaling and limiting cytokine release. Moreover, SHP2 is essential for anti-inflammatory M2 macrophage polarization (Figure 4). These contrasting roles highlight the compartment- and context-specific nature of SHP2 function: while cytosolic SHP2 in immune cells may suppress inflammation, mitochondrial SHP2 in vascular or stromal cells may exacerbate inflammation and senescence under stress conditions (Figure 5).

In the cardiovascular system, this functional dichotomy is particularly relevant. Mitochondrial SHP2-driven senescence has been linked to endothelial dysfunction, impaired angiogenesis, cardiomyocyte hypertrophy, and accelerated atherosclerosis [38,39]. However, SHP2 can also act protectively by inhibiting NLRP3 inflammasome activation and limiting mtROS, thereby preserving mitochondrial integrity (Figure 5). These protective effects may be compromised during ICI therapy, which can inhibit SHP2 activity either directly or indirectly by disrupting upstream signaling. As a result, the loss of SHP2's regulatory function may contribute to uncontrolled immune activation, oxidative stress, and cardiovascular toxicity [40]. These findings emphasize the importance of considering cell type specificity, subcellular localization, and therapeutic context when interpreting SHP2 function—and when targeting SHP2 in both cancer and vascular disease [41,42,43] (Figure 5).

PD-1 was first identified as a negative regulator of T cell activation in 1992 by Ishida et al. [42], and its role as a negative regulator was found to be linked to programmed death-ligand 1 (PD-L1) leading to the development of immune checkpoint blockade therapies [49]. The PD-1/PD-L1 axis was soon recognized as a valuable mechanism for tumor evasion of immune surveillance where T cell suppression leads to immune evasion [11]. Upon binding with PD-L1, PD-1 is phosphorylated at specific tyrosine residues, in the cytoplasmic immunoreceptor tyrosine-based switch motif (ITSM) and immunoreceptor tyrosine-based inhibitory motif (ITIM) [11,50]. Phosphorylation allows the protein SHP2 to be recruited to the receptor. The phosphorylated ITSM binds to the C-SH2 domain, while the phosphorylated ITIM binds to the N-SH2 domain to activate SHP2 (Figure 1 and Figure 2). Once recruited and activated, SHP2 will dephosphorylate proximal components of T cell receptor (TCR) signaling (like CD3ζ, ZAP70, PI3K), suppressing downstream cascades (like PI3K-AKT or Ras-ERK), depleting cytokine production (in particular, IL-2), and enforcing T cell anergy [51,52,53]. The SHP2-driven, immune suppressing cascade allows tumor cells to escape immune response and evade immune surveillance [53] (Figure 6).

SHP2, classically described as a positive mediator of proliferation and survival through Ras-MEK-ERK and PI3K-AKT pathways in non-immune lineages like endothelial and myeloid cells [10,54,55], is paradoxically a suppressive regulator in T cells [56]. In the instance of recruited SHP2 by inhibitory receptors (like PD-1 and CTLA-4), the suppressive role of SHP2 occurs by damping down TCR signaling and subsequent IL-2 production, while inhibiting the activation of downstream pathways (including NF-κB, NFAT, and mTOR) [17]. This is accomplished, in part, by SHP2 lowering the phosphorylation of CD28 and decreasing co-stimulatory engagement (via PI3K). Other inhibitory receptors (B- and T- lymphocyte attenuator, BTLA and T cell immunoglobulin and ITIM domain, TIGIT) also recruit SHP2 through ITIM domains that contribute to the maintenance of T cell exhaustion [17,18].

One reason is that PD-1 engagement pulls SHP2 away from its active substrates in the Ras/ERK pathway to diminish its ability to promote T cell activation and favors signal inhibition [57]. The evidence indicates that SHP2 function in T cells is contextual and in any given moment, SHP2 can promote or inhibit activation depending on the receptors it has engaged and the signaling context through which it has engaged T cells. This behavior is flexible and stimulus-dependent, thus allowing SHP2 to act as a master regulator of T cell function; consequently, this provides a unique opportunity to study SHP2 with conditional genetic-engineering approaches in animals. Conditional deletion of SHP2 in T cells with CD4-Cre (Ptpn11fl/fl; CD4-Cre) is providing evidence that SHP2 is not required for T cell exhaustion: Ptpn11-deficient mice in chronic viral infection or cancer/melanoma challenge did not display differing expressions of T cell exhaustion marker expressions and responses to anti-PD-1 treatment as compared to the wild-type or externally wild-type mice, suggesting that alternative phosphatases (e.g., SHP1) can mediate inhibitive signals in vivo [58]. The findings in the absence of Ptpn11 in mice expressing constitutively active SHP2 D61Y mutant, in conjunction with Lck-Cre or pTα-Cre, showed increased expression of PD-1 on CD4+ and CD8+ T cells, diminished proliferation, increased apoptosis, and altered memory T cell populations with increased effector memory and intact immune clearance of viral pathogens [59].

SHP1 (PTPN6) and SHP2 (PTPN11) are nearly identical family members in the class of tyrosine phosphatases, with the capability to regulate immune signaling based on binding phosphorylated ITIM/ITSM, with partially redundant and distinctly different functions. Using T cell-specific knockout models, it was found that both SHP1 and SHP2 redundantly constrained the differentiation of naïve T cells, predominately by SHP1; SHP2 loss alone enhanced anti-PD-1 therapy efficacy; however, dual loss of SHP1 and SHP2 leads to impaired tumor control as a result of CD4+ T cell activation-dependent cell death [60]. The dual contribution of SHP2 dysregulating tumor cell signals and inhibiting T cell function makes it a promising immuno-therapeutic target; for example, treatment of SHP2 inhibitor SHP099 was unchanged in tumor intrinsic model systems; however, it provided robust tumor burden reduction in immune composition mice through the induction of CD8+ T cell responses and increased expression of cytotoxic gene signatures. Moreover, SHP099 immuno-therapeutics in conjunction with anti-PD-1 therapy was more effective than either modality taken alone in models of colon cancer, suggesting that they have complementary effects [61]. Collectively these data support SHP2 as an important regulatory node in tumor immunity and a promising immuno-therapeutic agent that can be used to augment immune checkpoint inhibitor therapies.

Beyond its role in the inhibition of T cells, PD-1/SHP2 signaling has a significant impact on the development and function of myeloid cells. GM-CSF signaling promotes PD-1 activation via phosphorylation and promotes the recruitment of the PD-1–SHP2 complex by the receptor. Inhibition of PD-1 or SHP2 translates to increased downstream transcription factors, homeobox A10 (HOXA10) and interferon regulatory factor 8 (IRF8), that are essential for myeloid differentiation and commitment to the monocytic dendritic lineage. It has been reported that PD-1/SHP2 can act as a negative regulator of myelocyte differentiation and forms a myeloid environment to inhibit anti-tumor immunity [5] (Figure 6B).

In the tumor microenvironment (TME), macrophages are regulated by tumor-derived CSF-1, which binds to CSF-1R and promotes their survival and polarization into tumor-promoting phenotypes [62]. These tumor-associated macrophages (TAMs) facilitate tumor growth by suppressing immune responses and enhancing angiogenesis. SHP2, a tyrosine phosphatase activated downstream of CSF-1R, amplifies this signaling by promoting RAS/MAPK and PI3K/AKT pathways, thereby enhancing macrophage proliferation and polarization [61]. SHP2 may also contribute to increased CSF-1 or CSF-1R expression via ERK-dependent transcriptional regulation, forming a positive feedback loop that sustains TAM activation [10].

Additionally, immune checkpoint pathways such as CD47/SIRPα inhibit phagocytosis by delivering a "don't eat me" signal from tumor cells to macrophages. Li et al. [55] reported that SIRPα on tumor-infiltrating macrophages (TIMs) binds to CD47 on tumor cells, initiating a downstream signaling cascade that requires the deneddylation of SHP2. SHP2 is constitutively neddylated at lysine residues K358 and K364, maintaining it in an autoinhibited state. Upon CD47 engagement, SIRPα recruits SHP2, which is deneddylated by SENP8, leading to its activation and subsequent dephosphorylation of substrates at the phagocytic cup, thereby inhibiting phagocytosis. Functionally, SHP2 neddylation inactivates its suppressive role and enhances the efficacy of colorectal cancer (CRC) immunotherapy. Furthermore, SHP2 allosteric inhibition sensitizes immunotherapy-resistant CRC, particularly in tumors characterized by high SIRPα and SHP2 expression with low NEDD8 levels. These findings identify SHP2 as a critical immune checkpoint regulator and a promising therapeutic target in CRC, and this SHP2-mediated suppression of efferocytosis allows tumor cells to evade immune clearance and persist within the TME, contributing to tumor progression and resistance to immunotherapy [63] (Figure 6B).

Blockade of SHP2 could shift TAMs toward the anti-tumor M1 phenotype to promote immune response and show SHP2 to be a strong fulfillment target for immunotherapy. Further, instead of enhancing M1, SHP2 contributes to an immunosuppressive TME and can diminish anti-tumor immunity by promoting M2 macrophage activation and dampening T cells' response to ICIs. This suggests that myeloid cells have a role in therapy resistance and demonstrates that SHP2 can be a therapeutic target for ICI treatment [11,64,65]. ICI therapy can lead to potent, systemic immune activation with increased pro-inflammatory cytokines (IFN γ, TNF α, IL 6, and IL 1β) in a phenomenon sometimes described as a "cytokine storm". While these mediators promote anti-tumor immunity, their elevated levels may promote off-target tissue injury and increased inflammation that can lead to (myocarditis, vasculitis) and accelerated atherosclerosis [66]. Preclinical models have provided valuable mechanisms linking ICI therapy to cardiovascular irAEs. For example, Pdcd1^−/− BALB/c [67] mice developed autoimmune dilated cardiomyopathy spontaneously via the presence of anti-cardiac troponin I autoantibodies, CD4+ and CD8+ T cell infiltration, and heart failure [68,69]. PD-1 deficiency on autoimmune-prone backgrounds such as MRL-fas^lpr accelerates myocarditis and leads to fulminant cardiac inflammation [70,71].

The PD-1/PD-L1 immune checkpoint pathway was first implicated in vascular biology by Gotsman et al., who demonstrated that the genetic deletion of PD-1 or PD-L1 in Apoe^−/− mice resulted in significantly larger, more inflamed, and unstable atherosclerotic plaques [72]. This pivotal study identified PD-1 signaling as a critical negative regulator of T cell-driven vascular inflammation, acting as an "immune brake" to prevent excessive immune activation in the vessel wall. Subsequent research has shown that PD-1 plays a broader role in maintaining vascular homeostasis. In atherosclerosis-prone models, PD-1 blockade accelerates disease progression by enhancing T cell activation, monocyte recruitment, foam cell formation, and endothelial dysfunction—key processes in plaque development and destabilization [73,74,75]. In particular, both single cell RNA sequencing and mass cytometry approaches have mechanistically extrapolated that T cells, specifically cytotoxic CD8+ T cells and Th1-polarized CD4+ T cells, accumulate within atherosclerotic plaques (in both humans and mice) and these T cells contribute to necrotic core formation and plaque instability [76]. For example, in Ldlr^−/− mice, CD8+ T cells contribute to atherosclerosis by promoting early monopoiesis and macrophage cell death; upon CD8+ T cell depletion, atherosclerosis was lessened [72,73]. PD-1-deficient models likewise showed these effects, which included a predominant CD8+ T cell immune response signaling a form of cell necrotic pathway.

PD-1 signals through SHP2, a phosphatase that also regulates macrophage activation. Recent studies show that SHP2 inhibition or deletion in macrophages exacerbates atherosclerosis in ApoE^−/− and Ldlr^−/− mice by increasing inflammation, impairing efferocytosis, and destabilizing plaques. Mechanistically, SHP2 stabilizes PPARγ, a transcription factor essential for anti-inflammatory macrophage function, which is degraded upon SHP2 loss [77]. PD-1/SHP2 signaling also influences myeloid cell differentiation, as shown in tumor models where PD-1-SHP2 restrains GM-CSF-mediated activation of transcription factors like HOXA10 and IRF8 [5]. These findings suggest that PD-1/SHP2 signaling in macrophages plays a protective role in atherosclerosis by limiting inflammation and promoting resolution through PPARγ stabilization and regulated myeloid differentiation (Figure 6B).

Together these data suggest that PD-1/SHP2 signaling regulates myeloid differentiation, inflammatory tone, and vascular immune homeostasis. The disruption of PD-1/SHP2 signaling via genetic ablation or blockade of immune checkpoints adds to myelopoiesis, and macrophage polarization to pro-inflammatory macrophage, and pathological myeloid–T cell interaction leading to atherosclerosis, myocarditis, and vasculitis. Our understanding of these pathways in mouse models led to important insights and provided some framework by which we can predict, detect, and manage cardiovascular irAEs. Future studies of the dynamics of checkpoint signaling in tissue resident myeloid compartments will be important to enhance immunotherapies while preserving cardiovascular health.

The deletion or silencing of SHP 2 specifically in ECs, or endothelial cells, increased the expression of adhesion molecules ICAM-1 and VCAM-1, increasing leukocyte adhesion and loss of endothelial barrier function, defining the features of early vascular inflammation [78]. In these settings, SHP 2 inhibits the association of ICAM-1 and VE cadherin-β catenin complexes, which provides a basis for regulating leukocyte transmigration and the dynamic re-assembly of the endothelial junctions [78]. Based on the soluble PD 1 receptors at the immune checkpoint directly recruiting SHP 2 through the specific motif ITIM/ITSM in the cytoplasmic tail, SHP 2 is an important signal transducer in PD 1 immune checkpoint signaling [11]. While PD-1 is more known for its immunosuppressive role on T cells, its function within ECs can be different.

SHP2 plays a central role in maintaining endothelial cell homeostasis by stabilizing the endothelial barrier and limiting inflammatory signaling under physiological conditions [78,79]. Through its regulation of junctional integrity and downstream signaling pathways, SHP2 helps preserve vascular quiescence and prevents leukocyte infiltration [79]. Therefore, in the presence of oxidative stress, such as hydrogen peroxide (H₂O₂) exposure, SHP2 inactivates and promotes inflammation due to the upregulation of the adhesion molecules ICAM-1 and VCAM-1, which promote monocyte adhesion to the endothelium [80]. Oxidative stress leads to H₂O₂-induced crosstalk between SHP2 and PP2A, which activates the crosstalk between SHP2 and PP2A and increases NF-κB signaling, which ultimately favors sustained endothelial–leukocyte crosstalk [81]. In inflammatory conditions, such as when ROS generation is induced from cholesterol crystals, the inactivation of SHP2 augments NF-κB-driven adhesion molecule gene transcription that drives vascular inflammation [82] (Figure 7A).

However, under pathological stress such as radiation exposure, SHP2 signaling may become maladaptive. Emerging evidence suggests that radiation can increase SHP2 activity, leading to endothelial dysfunction, increased permeability, and heightened inflammatory responses. In the clinically relevant radiation-induced lung injury (RILI) murine model characterized by progressive endothelial dysfunction and progressive fibrosis, SHP2 activity was measured to be elevated in ECs post thoracic irradiation. Endothelial-specific deletion of SHP2 resulted in reduced collagen deposition and dysregulated expression of Jagged 1 (Jag1), a Notch ligand shown to modulate macrophage polarization. Mechanistically, EC-derived Jag1 activates alternative macrophage polarization through Notch signaling in a paracrine fashion, creating a pro-fibrotic immune environment. This pathway was determined to be active in peripheral leukocytes from cancer patients following chest irradiation, supporting the potential relevance and clinical translational applicability. In summary, these results suggest that while SHP2 supports vascular stability and homeostasis in healthy tissues, the upregulation of SHP2 in vascular tissue in response to radiation stress may be detrimental by promoting vascular inflammation and fibrosis, supporting SHP2 as a context-dependent therapeutic target in radiation-induced vascular injury [83]. It is also important to consider that this pathogenic effect may occur via mitochondrial activation of SHP2 as a consequence of radiation damage, as detailed in Section 2.2, but a thorough characterization of this mechanism is still required (Figure 7A).

Wang et al. [41] demonstrated that PD-1/PD-L1 signaling plays a protective role in hypoxia-induced pulmonary hypertension (HPH), a condition driven by Th17-mediated inflammation. Their study showed that PD-1/PD-L1 expression is downregulated in HPH, particularly in endothelial cells, and that PD-1-deficient mice developed more severe disease under hypoxia. The restoration of PD-L1, either through recombinant protein or endothelial overexpression, alleviated HPH, while PD-L1 blockade enhanced endothelial angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia-induced PD-L1 downregulation occurred via ubiquitination, and PD-L1 suppressed Th17 responses through the PI3K/AKT/mTOR pathway. Although the role of SHP2 in PD-1/PD-L1-mediated endothelial protection remains to be fully defined, these findings suggest that PD-1-dependent SHP2 signaling may contribute to endothelial stability. Importantly, this raises concern that ICIs, which block PD-1/PD-L1 interactions, could disrupt endothelial homeostasis and promote vascular dysfunction. Further investigation is needed to clarify the mechanisms by which PD-1/SHP2 signaling modulates endothelial responses in both physiological and pathological contexts.

SHP2 was recognized as a pro-atherogenic mediator in vascular smooth muscle cells (VSMCs) through its role in mitogenic signaling. For example, Chen et al. showed in Ldlr^−/− mice given a high-cholesterol diet that pharmacological blockade of SHP2 with phenylhydrazonopyrazolone sulfonate 1 (PHPS1) reduced ERK phosphorylation, inhibited VSMC proliferation, and reduced neointimal thickening. Together, these findings suggest that targeting SHP2 in VSMCs to modulate the SHP2–ERK signaling pathway may be an athero-protective strategy by potentially controlling pathological vascular remodeling [84] (Figure 7B).

SHP2 demonstrates varied and context-dependent effects on atherosclerosis that change quite substantially across different vascular and immune cell types (Table 1, Table 2 and Table 3). In macrophages, SHP2 is overall considered athero-protective, facilitating M2-like polarization and anti-inflammatory properties, which promote plaque stability. The inhibition of SHP2 or loss of SHP2 in macrophages has been associated with increased inflammation and foam cell formation, accelerating disease progress. In T cells, SHP2 functions in a PD-1-dependent manner, acting downstream of PD-1 to inhibit T cell receptor signaling, and limiting excessive immune activation. While this PD-1 function is beneficial to maintaining immune balance iatherosclerosis, chronic activation of PD-1 signaling via SHP2 can promote an exhausted T cell phenotype, further limiting anti-inflammatory resolution in atherosclerosis plaques.

In VSMCs, however, SHP2 functions as a pro-atherogenic effector, promoting and amplifying ERK/MAPK signaling pathways that promote proliferation, migration, and neointimal formation, all of which are key contributors during plaque formation. Importantly, pharmacological inhibition of SHP2 in VSMCs using PHPS1 showed reduced intimal hyperplasia and better plaque composition in mice. For endothelial cells, SHP2 also possesses a dual, context-dependent function in vascular inflammatory regulation. In contexts of oxidative stress (H₂O₂ and cholesterol crystals), SHP2 becomes inactivated, which promotes the upregulation of adhesion molecules including ICAM-1 and VCAM-1 and facilitates monocyte recruitment to the endothelium. In contrast, although exposure of endothelial cells to total body radiation activates SHP2, radiation increased inflammation by upregulating adhesion molecule expression and activation of downstream inflammatory pathways including Notch-Jag1 signaling, ultimately contributing to leukocyte infiltration, macrophage polarization, and fibrotic remodeling. Furthermore, VSMC and mitochondrial SHP2 may trigger pro-atherogenic effects. Collectively, these studies highlight the complex, stimulus-dependent nature of SHP2 signaling for endothelial biology where both suppression and activation can drive vascular inflammation and dysfunction depending on context. SHP2 is remarkable as a complex signaling hub and the atherosclerotic implications of SHP2 actions in each affected cell type are nuanced and context-dependent. This is important to address when developing cell type-specific targeted therapeutic strategies.

ICIs such as anti-PD-1 or anti-PD-L1 antibodies are utilized to block PD-1/SHP2 signaling in T cells to enhance anti-tumor immunity. While ICIs have been effective in treating a wide range of cancers, they not only block PD-1/SHP2 signaling in T lymphocytes, but also in endothelial cells and other non-immune cells. Removal of this regulatory mechanism by SHP2 may also lead to adjusted endothelial activation, increased leukocyte infiltration into tissues, and vascular inflammation. These effects, unintended, exacerbate atherogenesis, or can trigger cardiovascular irAEs, such as myocarditis, vasculitis, or plaque destabilization, which are increasingly being reported in patients receiving ICI therapy. Based on the variety of roles SHP2 plays in vascular biology, precise targeting of SHP2 for therapeutic purposes is needed. For instance, while the inhibition of SHP2 in VSMCs could have beneficial effects on reducing restenosis/neointimal formation, the inhibition of SHP2 in endothelial cells or macrophages could potentially exaggerate vascular inflammation. Future directions could look into cell type-specific targeting of SHP2, conditional knockout models, or local drug delivery systems. Furthermore, for patients undergoing ICI therapy as part of cancer treatment, cardiovascular monitoring may yield valuable opportunities for detection along with preservation strategies to preserve endothelial SHP2 signaling to mitigate long-term vascular adverse events. As the nexus of inflammation, immunity, and vascular disease, the modulation of SHP2, particularly in a cautiously crafted manner, may offer a chance to enhance oncological efficacy, while mitigating cardiovascular adverse events.