Tumor microenvironments (TME) are usually immunosuppressive and prevent lymphocyte priming. Recent clinical trials have shown that cancer immunotherapy such as immune checkpoint inhibitors can induce unprecedented durable responses in patients with a variety of cancers. Tertiary lymphoid structures (TLS) can form inside or adjacent to tumor tissues due to persistent inflammation. The formation of TLS facilitates lymphocyte trafficking and infiltration into tumor tissues. It can also support effective antigen presentation and lymphocyte activation. Thus, TLS have become an intriguing target to manipulate antitumor immunity. Several therapeutics targeting TLS have been developed and shown promising antitumor effects in various mouse models. In this chapter, we describe the general approach to establish transplantable mouse tumor models for the study of immunotherapy. We introduce the strategies for therapy through systemic or local treatment targeting TLS. We also present approaches to evaluate the antitumor immune responses provoked by the therapies.