This study investigates the role of CD276, an immune checkpoint molecule expressed on tumor-associated macrophages (TAMs), in bladder cancer (BLCA). CD276 is found to promote immune evasion by enhancing efferocytosis, which reduces the expression of major histocompatibility complex class II (MHCII) on TAMs and impairs the infiltration of cytotoxic CD8+ T cells. Genetic ablation of CD276 in TAMs blocks efferocytosis, increases MHCII expression, and enhances tumor growth inhibition in a mouse model of BLCA. Single-cell RNA sequencing reveals that CD276 activates the lysosomal signaling pathway and transcription factor JUN, leading to increased expression of AXL and MerTK, which are crucial for efferocytosis. Simultaneous blockade of CD276 and PD-1 further improves tumor growth inhibition, suggesting a potential synergistic effect of these therapies. The findings highlight the importance of targeting CD276 in combination with other immune checkpoint inhibitors for effective immunotherapy in BLCA.This study investigates the role of CD276, an immune checkpoint molecule expressed on tumor-associated macrophages (TAMs), in bladder cancer (BLCA). CD276 is found to promote immune evasion by enhancing efferocytosis, which reduces the expression of major histocompatibility complex class II (MHCII) on TAMs and impairs the infiltration of cytotoxic CD8+ T cells. Genetic ablation of CD276 in TAMs blocks efferocytosis, increases MHCII expression, and enhances tumor growth inhibition in a mouse model of BLCA. Single-cell RNA sequencing reveals that CD276 activates the lysosomal signaling pathway and transcription factor JUN, leading to increased expression of AXL and MerTK, which are crucial for efferocytosis. Simultaneous blockade of CD276 and PD-1 further improves tumor growth inhibition, suggesting a potential synergistic effect of these therapies. The findings highlight the importance of targeting CD276 in combination with other immune checkpoint inhibitors for effective immunotherapy in BLCA.