A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC including patients outside of traditional resection criteria (NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin negative resection, and 5/12 (42%) patients had major pathologic responses. In-depth biospecimen profiling demonstrated an enrichment in T effector cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders as compared to non-responders, indicating an orchestrated B-cell contribution to antitumor immunity in HCC.