Abstract Immunotherapy has stolen the spotlight as one of the most promising therapeutic strategies for many late stage cancers. Despite exhibiting immense potential, dendritic cell (DC) based immunotherapy has shown limited clinical benefits owing to the antagonistic effects of regulatory T cells. While regulatory T-cells dampen the immune response elicited by T effector cells through known control mechanisms, they also constitute an immune suppressive milieu with several other tumor-derived factors that impair the development and maturation of dendritic cells. This serves as a mechanism for the tumor cells to escape immune surveillance and control. It is well known that inhibition of the JAK2/STAT-3 and p38 MAPK pathways in DCs negates the tumor-induced suppression of their maturation. But it has been shown that inhibition of the STAT-3 pathway alone could counteract the suppressive effects of Interleukin-6 only and inhibition of the p38 MAPK pathway in cancer cells can be counterproductive as it is important for apoptosis. Thus it becomes essential that, to achieve a superior therapeutic response it is imperative to couple the inhibition of STAT-3 along with p38 MAPK pathway and to also ensure that it is targeted towards dendritic cells of the tumor microenvironment. We have catered to these necessities in this study by proposing a novel, supramolecular 2-in-1 nanomedicine designed by the self-assembly of patient compatible lipids that houses a STAT-3 inhibitor and a p38-α inhibitor , thus ensuring the deterministic delivery of both the drugs in a spatially constrained manner. We have shown that the 2-in-1 nanomedicine achieves superior efficacy by releasing both the drugs in a sustained manner during the differentiation of DCs and hence upregulates dendritic cell maturation markers like CD80, CD86 and MHC II. More importantly we aim to program the drug-loaded nanoparticles for selective uptake by dendritic cells of the tumor milieu. In a separate experiment we have shown that dendritic cells favor the uptake of nanoparticles with specific surface charges both in vitro and in vivo in B16F10 mouse melanoma model. Thus we conclude that the proposed 2-in-1 “sniper” nanoparticle can contribute immensely towards a targeted immunotherapy approach for rescuing dendritic cells from immune suppression in aggressive cancers like melanoma. Note: This abstract was not presented at the conference. Citation Format: Siva Kumar Natarajan, Vineethkrishna Chandhrasekar, Noha Ismail, Sharada Swaminathan, Shiladitya Sengupta, Ashish Kulkarni. 2-in-1 “sniper” nanomedicines rescue dendritic cells by two pronged inhibition of JAK2/STAT-3 and p38 MAPK pathways. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B52.