Systematically identifying synergistic combinations between targeted agents and immunotherapies in cancer based on genomic or other static biomarkers remains elusive. Here we integrate two novel high-content and high-throughput techniques, an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses; and spatial systems analysis of tumor microenvironmental states to describe tumor cell and immunological response signatures and rapidly, within days, identify effective combinations from among numerous agents. We demonstrate in systemic follow-up studies across three mammary carcinoma models that combinations identified by this approach lead to highly synergistic effects. Biomarkers associated with resistance to each agent allowed us to prioritize at least five novel treatment strategies of which the panobinostat/venetoclax/anti-CD40 was the most effective inducing complete tumor control across models. We show that spatial association of cancer stem cells with dendritic cells during immunogenic cell death is a potential mechanism of action underlying long-term breast cancer control.