Simple Summary: The clinical efficacy of immunotherapies when treating cold tumors is still low, and different treatment combinations are needed when dealing with this challenging scenario. In this work, a middle-out strategy was followed to develop a model describing the antitumor efficacy of different immune-modulator combinations, including an antigen, a toll-like receptor-3 agonist, and an immune checkpoint inhibitor in mice treated with non-inflamed tumor cells. Our results support that clinical response requires antigen-presenting cell activation and also relies on the amount of CD8 T cells and tumor resistance mechanisms present. This mathematical model is a very useful platform to evaluate different immuno-oncology combinations in both preclinical and clinical settings. Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm(3) and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8(+) T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.