Chemotherapy, together with radiotherapy, targeted therapies, and immunotherapy, is the main option to treat cancer patients in neoadjuvant/adjuvant setting to reduce the risk of disease progression and metastasis formation from disseminated tumor cells. Cancer cells that survived chemotherapy treatment may emerge with novel characteristics, one of which is the ability to stimulate the native and adaptive immune systems. Models allowing the characterization of chemotherapy-induced tumor cell plasticity and induction of immune response or adaptation are needed to identify novel mechanisms and devise novel therapeutic strategies to prevent relapses. Here we describe a protocol for selecting chemotherapy-resistant cancer cells and testing the in vivo effects on the local and systemic immune responses. While originally developed to characterize the effects of methotrexate and doxorubicin on murine 4T1 breast cancer cells and the relative immune response, the method can be broadened to other chemotherapies and syngeneic cancer models.