A deeper understanding of orchestrated host-disease responses is needed to elucidate mechanisms of immunological response, such as immunomodulation of viral infections and cancer. The development of the new "spatial-omics" tools now allows us to address previously unanswerable fundamental questions, allowing mechanistic dissection of cell states and identifies in situ. Here, I will demonstrate several published, in press, and unpublished novel experimental and computational frameworks and their applications for a systems-level understanding of the immune-disease interface in their native tissue context. By combining technology development with the questions above, we will decipher higher-order host-disease interactions to understand disease mechanisms, with the long-term goal of improving therapeutics.