Zanzalintinib (XL092) 是新一代抗 VEGFR 相关多靶点 TKI，具有免疫调节作用。本综述探讨了 zanzalintinib 的临床前和临床数据，以及与 zanzalintinib 及其与免疫检查点抑制剂 (ICIs) 联合用药相关的未来方向。除了其抗 VEGFR 活性外，zanzalintinib 通过其免疫调节作用表现出与 ICI 的潜在协同作用，这归因于其对 MET 和 TAM 激酶的抑制。最近的临床前研究提供了令人信服的证据支持这种协同潜力。此外，最近的一项 1 期剂量递增研究证实了 zanzalintinib 和抗 PDL1 组合的耐受性，没有重大安全问题。多项正在进行的临床试验正在研究 zanzalintinib 和 ICI 的组合在各种实体瘤类型中的应用，包括针对肾细胞的 3 期研究癌、结直肠癌和头颈癌。这些试验旨在阐明这种新一代 TKI 和 ICI 组合的治疗作用。然而，为 zanzalintinib 和 ICI 组合确定可靠的预测生物标志物提出了重大挑战。鉴于其机制原理的复杂性以及识别抗血管生成和 ICI 联合疗法的可靠生物标志物的困难，解决这一挑战仍然是正在进行和未来研究的优先事项。

Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects.This review explores preclinical and clinical data, along with the future directions associated with zanzalintinib and its combination with immune checkpoint inhibitors (ICIs).In addition to its anti-VEGFR activity, zanzalintinib demonstrates potential synergistic effects with ICIs through its immunomodulatory impact, attributed to its inhibition of MET and TAM kinases. Recent preclinical studies provide compelling evidence supporting this synergistic potential. Furthermore, a recent phase 1 dose escalation study confirmed the tolerability of the zanzalintinib and anti-PDL1 combination without major safety concerns.Multiple ongoing clinical trials are investigating the combination of zanzalintinib and ICIs across various solid tumor types, including phase 3 studies for renal cell carcinoma, colorectal, and head and neck cancer. These trials aim to elucidate the therapeutic role of this new-generation TKI and ICI combination.However, the identification of reliable predictive biomarkers for the zanzalintinib and ICI combination presents significant challenges. Given the intricate nature of their mechanistic rationale and the difficulties in identifying reliable biomarkers for combined anti-angiogenesis and ICI therapies, addressing this challenge remains a priority for ongoing and future research.