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The short-time (hours to few days) response of solid tumors to either targeted inhibitors or to immunotherapy treatments has been a subject of increasing importance with respect to understanding non-genetic (adaptive) responses to therapeutic perturbations, and for understanding how to  exploit those responses to increase the drug susceptibility via sequential therapies.  The short-time responses are dictated by the intricate interactions of different cell types in the tumor ecosystem where the lead-in therapy can ‘prepare’ the tumor-immune microenvironment (TIME) for killing when subsequent therapy is added. To understand optimal and sub-optimal response patterns of distinct sequential-combinatorial regimens in various clinical trials, we resolve the cancer biology that happens following short-term lead-in therapy with cutting-edge spatiotemporal multi-omics tools, and then feed the results into innovative computational models to simulate the dynamic evolution of TIME to yield deeper insights (and novel hypotheses) of the underlying biology for experimental validation, with the goal to understand how to design sequential-combinatorial therapy that can  promote a strong anti-tumor response.