Macrophages are highly plastic cells that are a part of the mononuclear phagocytic system and play a crucial role in both the innate and the adaptive immune systems. Although they have functionally diverse roles involved in physiological and pathological processes, they primarily act as phagocytes that aid in clearing infections. During these instances of tissue injury or infections, circulating monocytes are recruited to the site of the injury, where they differentiate to give rise to macrophages that have a pro-inflammatory function. These monocytes derived macrophages, however, exist across a spectrum of phenotypes based on the local tissue environment. The two ends of the spectrum are defined by a pro inflammatory M1 phenotype and an immunosuppressive, anti-inflammatory M2 phenotype. Given the highly immunosuppressive role played by TAMs in exacerbating tumor progression, we can hope to effectively exploit the inherent plasticity of macrophages by “re-educating” TAMs from an M2 phenotype to anti tumorigenic M1 phenotype. To realize this goal, it is essential to conceive therapeutic strategies aimed at targeting signaling pathways involved in macrophage activation. Current strategies to measure immunological response rates in macrophage centric clinical trials rely on anatomical measurements involved in evaluating the RECIST criteria such as computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose–positron emission tomography (FDG–PET). These techniques lack sensitivity and specificity to detect early response against different macrophage immunotherapies. Therefore, there is an immediate need to identify novel tools that can detect cellular and molecular changes associated with macrophage-based cancer therapy in a sensitive and noninvasive manner during the treatment, that could initiate a paradigm shift in the field of immunodiagnostics for macrophage immunotherapy. Given the above-mentioned concerns in the field of macrophage immunology, we propose to address these gaps by developing novel approaches for establishing nanoparticle-based systems efficient in not only designing effective drug delivery strategies aimed at reprogramming TAMs, but also design diagnostic systems that can monitor macrophage activation states to predict disease progression and therapeutic efficacy.