In spite of fundamental role of angiogenesis in fetal development and in many physiological conditions like wound healing tumors exploit it to promote blood vessel growth and fuel a tumor’s transition from benign to a malignant state. Likewise, these malignant transformations need evasion from XL-184 inhibitor immune destruction, which has been included recently, in 2011, as another important hallmark of cancer growth. Angiogenesis and immune evasion, these two apparently parallel cancer-intrinsic phenomenon actually possess bidirectional link and convergely promote malignant growth, metastasis and ultimately regulate therapeutic outcome. In cancer, immune system can regulate angiogenesis with both pro- and anti-angiogenic activities. Angiogenic molecules by differentially regulating immune system help in the development of sustained immunosuppressive mechanisms within tumor microenvironment. This immunosuppressive mechanism may promote angiogenesis and tumor growth and inhibits infiltration and homing of activated immune cells within TME. Promoted angiogenesis then deregulates the proliferation and migration of vascular endothelial cells, thereby, causing neovascularization. These results in aberrant tumor vasculature associated with distorted and enlarged vessels, increased permeability, irregular blood flow and micro-hemorrhages. Therefore, in recent years different works have shown that, for optimum immune-mediated tumor destruction, normalization of tumor vasculature is preferred over complete blockade of tumor angiogenesis. Neem leaf glycoprotein, a nontoxic immunomodulator reported previously have significant murine tumor growth restricting potential in prophylactic as well as therapeutic settings. Therefore, in the present study, we prophylactically applied NLGP in murine carcinoma and melanoma bearing mice to boost antitumor immune responses and subsequently analyzed the mode of NLGP counteraction on the tumor angiogenesis. We report that NLGP pretreatment associated immune-stimulation, particularly CD8+ T cell activation, regulates the balance between pro- and anti-angiogenic molecules to induce vascular normalization without affecting normal physiological angiogenesis. We have reported significant restriction of murine sarcoma, carcinoma and melanoma growth due to administration of NLP/ NLGP in prophylactic and therapeutic settings. This tumor growth restriction is strictly dependent upon modulation of host-tumor immune interaction, since NLGP is unable to induce direct tumor cell apoptosis. Apart from the already discussed immunomodulation by NLGP in cancer, angiogenic normalization property of this molecule is described here for the first time. As results suggest, prophylactic administration of NLGP is inhibitory towards neovascularization initiated after tumor challenge and the antiangiogenic effect is indeed associated with the decrease in heavily dilated /fragile as well as very thin blood vessels. Under NLGP influence, their tight association with VECs restore the vessel integrity and prevents leakiness. Therefore, by differentially regulating the two important stromal cell features, NLGP controls aberrant tumor vasculature. In context to hostantitumor benefits such results are encouraging as recent preclinical and clinical findings suggest that vascular normalization, rather than restriction of blood flow, is necessary to maintain the surge of effector immune cells and chemical regimens for cancer therapy. Evidences are accumulated from present study suggesting the interference of NLGP in balancing tumor growth-supportive proand anti-angiogenic molecules.