CD276 expressed on tumor-associated macrophages (TAMs) promotes immune evasion in bladder cancer. The study shows that CD276 in TAMs reduces the immune response against tumors by enhancing efferocytosis. Genetic ablation of CD276 in TAMs blocks efferocytosis and increases MHCII expression, leading to increased infiltration of CD4+ and CD8+ T cells. Single-cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN, regulating AXL and MerTK expression, which enhances efferocytosis in TAMs. Blocking CD276 and PD-1 together is more effective than either alone in inhibiting tumor growth. CD276 is a promising target for combination immune therapy in bladder cancer. CD276 is a member of the B7 family and is expressed in tumor cells, dendritic cells, and macrophages. Its expression is associated with poor prognosis in bladder cancer patients. CD276 knockout in mice reduces tumor growth and increases T cell infiltration. CD276 depletion in TAMs inhibits efferocytosis, leading to increased MHCII expression and T cell infiltration. CD276 promotes efferocytosis by regulating AXL and MerTK expression. CD276 blockade in TAMs enhances T cell infiltration and reduces tumor growth. Combination therapy with CD276 and PD-1 blockade is more effective than either alone. CD276 is a promising target for combination immune therapy in bladder cancer.CD276 expressed on tumor-associated macrophages (TAMs) promotes immune evasion in bladder cancer. The study shows that CD276 in TAMs reduces the immune response against tumors by enhancing efferocytosis. Genetic ablation of CD276 in TAMs blocks efferocytosis and increases MHCII expression, leading to increased infiltration of CD4+ and CD8+ T cells. Single-cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN, regulating AXL and MerTK expression, which enhances efferocytosis in TAMs. Blocking CD276 and PD-1 together is more effective than either alone in inhibiting tumor growth. CD276 is a promising target for combination immune therapy in bladder cancer. CD276 is a member of the B7 family and is expressed in tumor cells, dendritic cells, and macrophages. Its expression is associated with poor prognosis in bladder cancer patients. CD276 knockout in mice reduces tumor growth and increases T cell infiltration. CD276 depletion in TAMs inhibits efferocytosis, leading to increased MHCII expression and T cell infiltration. CD276 promotes efferocytosis by regulating AXL and MerTK expression. CD276 blockade in TAMs enhances T cell infiltration and reduces tumor growth. Combination therapy with CD276 and PD-1 blockade is more effective than either alone. CD276 is a promising target for combination immune therapy in bladder cancer.