Patients with solid cancers exhibit impaired humoral immunity, yet the underlying B cell–intrinsic mechanisms remain incompletely characterized. Here, we leveraged longitudinal SARS-CoV-2 vaccination as a model of defined antigen exposure to dissect B cell responses in cancer patients. Despite preserved early expansion following booster vaccination, cancer patients failed to sustain long-term durability and variant breadth of antigen-specific B cell responses. This defect was associated with reduced resting-memory (CD21⁺CD27⁺) and germinal center–derived (CD27⁺IgG⁺) subsets, along with a shift toward double-negative 2/3 populations. Single-cell transcriptomic and B cell receptor (BCR) repertoire analyses revealed reduced somatic hypermutation across antigen-specific B cell subsets and enrichment of a transcriptionally distinct atypical T-bet+ B cell cluster in cancer patients, collectively indicating impaired germinal center-associated maturation as a central B cell–intrinsic defect. Notably, a fourth vaccine dose restored long-term B cell maintenance, supporting proactive booster vaccination strategies for cancer patients.