Endovascular treatment has been fundamentally transformed the management of acute ischemic stroke (AIS). However, a prominent clinical challenge persists: almost half of the patients who have achieved successful recanalization of the occluded vessel fail to achieve the expected neurological improvement, a phenomenon termed "futile recanalization". In recent years, the combination of neuroprotective drugs with recanalization therapy has offered some new hope for this issue. Notably, combining immunomodulators with revascularization has shown potential to mitigate ischemia-reperfusion injury and reduce the risk of futile recanalization, providing novel clinical intervention strategies. Therefore, this review synthesizes the basic mechanisms of futile recanalization and new progress in this field. By employing a "vascular-immune-neural network" model to integrate various neuroprotective therapies, we aim to provide theoretical support for overcoming this challenge of AIS and improving the long-term prognosis of AIS patients.