Impact of synbindin deficiency on immune checkpoint blocker–induced systemic inflammation and multi-organ damage.

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12139 Background: Immune-related adverse events (irAEs) are a major safety limitation for the broad application of immune checkpoint blockade (ICB) in oncology, yet their precise molecular mechanisms remain unclear. Synbindin, a tethering-associated protein involved in vesicular trafficking and related processes, plays a key role in immune-cell activation and activation of inflammatory signaling pathways and therefore may represent an important initiator and predictive factor for irAEs. Methods: We generated constitutive whole-body Trappc4 knockout (Trappc4-KO) C57BL/6 mice and administered either anti-PD-1 monotherapy or combined anti-PD-1 plus anti-CTLA-4 immune checkpoint blockade via intraperitoneal injection. Plasma biochemical indices and the extent of organ injury were assessed following treatment. Results: Trappc4-KO mice receiving combined anti-PD-1/anti-CTLA-4 treatment exhibited markedly more severe immune-related toxicity and multi-organ injury than wild-type controls. Biochemically, markers of hepatic injury (AST, ALT) were substantially elevated, indicating liver dysfunction; renal function markers (serum creatinine and blood urea nitrogen) were significantly increased, consistent with kidney injury; and cardiac markers (CK-MB, cTnT, cTnI) were also markedly raised. A similar trend, although less pronounced, was observed following anti-PD-1 monotherapy. Histopathological examination corroborated these findings: H&E sections of affected organs showed prominent focal immune cell infiltration, cellular swelling, and areas of necrosis. Conclusions: These data demonstrate that Trappc4 deficiency significantly exacerbates ICB-induced systemic inflammation and multi-organ damage, suggesting that Synbindin plays a critical protective role in the development of irAEs.

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