Tumor and residing stromal cells secrete several growth factors particularly VEGF to stimulate VEGFR+ endothelial cell proliferation and in turn these cells provide the lining of newly formed blood vessels to supply nutrient to growing tumor. Among all VEGFRs, VEGFR2 is mainly found on newly proliferating endothelial cells and targeting of VEGFR2 has been shown in some tumor models to reverse neo-vascularization. Accordingly, NLGP selectively targets the VEGF-VEGFR2 signaling in proliferating endothelial cells to create a ‘vascular normalization window’ that might facilitate a decrease in interstitial pressure, enhanced tumor oxygenation and ultimately leads to a better therapeutic response in terms of restricted tumor growth. In view of our consistent observation on central involvement of immune system in NLGP-mediated eradication or prevention of murine tumor growth, the LDK378 present study additionally evaluated the involvement of NLGP-instructed immune-modulation in controlling tumor-angiogenesis. Interestingly, we observed a significant abolition of NLGP mediated both anti-angiogenic and anti-tumor effect in cyclosporine treated mice having prominent immunosuppression. However, adoptive transfer of immune cells from mice with NLGP therapy again restores both anti-angiogenic and tumor growth restricting effects of NLGP. Analysing these data, we speculated that NLGP-driven immune activation might be involved in anti-angiogenic process. To further validate our hypothesis, we used immunocompromised athymic nude mice and here also NLGP prophylaxis was unable to prevent neovascularization as well as tumor growth. Next, we directly focussed on the contribution of CD8+ effector T cells, since NLGP selectively increases the trafficking of these effector cells into tumor parenchyma and therapeutic NLGP mediated tumor growth restriction is abrogated completely in CD8+ T cell depleted mice. However, infiltrating CD8+ T cells often unable to show cytotoxic effect because, several tumor microenvironmental factors upregulate expression of inhibitory molecules like PD1 and CTLA4 on T cells to attenuate its effector functions and effector cytokine production. In this context, modulatory effect of NLGP on TME is already reported. More importantly, NLGP minimizes TME-induced anergy and exhaustion of CD8+ T cells and exhaustion related molecules TIM3, LAG3, PD1 and CTLA4 to preserve the optimum functional efficacy of infiltrated CD8+ T cells. Likewise, in present study, NLGP administration followed by CD8+ T cell depletion was unable to produce anti-angiogenic effect, as dilated tortuous blood vessels are seen in these groups of animals. Moreover, NLGP mediated reduction of proliferating CD31+ endothelial cells or VEGF-VEGFR2 expression within tumor is abrogated in CD8+ T cell depleted tumor bearing mice. In summary, our results suggest that NLGP prophylaxis educate whole immune system in such a way that after tumor challenge antigen presenting cells efficiently prime effector CD8+ T cells, which in due course kill tumor cells to reduce tumor promoting growth factor burden within TME. These reduced availability of growth factor especially VEGF subsequently impede the growth of endothelial cells without affecting the vessel integrity to maintain the proper trafficking of immune effector cells within TME. Among marine algae polysaccharide-based biomaterials, alginate is currently used in biomedical and pharmaceutical areas for wound dressing, as an ointment for burns, or as a formulation aid in controlled drug delivery systems. Thanks to its biosafety and biocompatibility, alginate is also commonly used for tissue and cell immobilization by means of a bioencapsulation process.