CDK2 and neoplasm: Here, we demonstrate that Cdk2-/- tumor cells not only sensitize MTX-induced ICD to drive the expression of ICD hallmarks, stimulate immune cell infiltration, and inhibit tumor growth but also enhance the effects of anti-PD-1 therapy to provoke a robust anticancer immune response, result in enhanced anti-tumor immunity, culminating in tumor regression, suggesting a synergistic therapeutic relationship.