Single-cell RNA sequencing unveils enhanced antitumor immunity in colorectal cancer with PD-1 blockade and LINC00673 deletion.

BACKGROUND: Most colorectal cancers are resistant to immune checkpoint inhibitors due to an immunosuppressive tumor microenvironment. LINC00673, previously classified as a long non-coding RNA, has been implicated in tumor progression, but its role in antitumor immunity remains poorly understood. METHODS: We used single-cell RNA sequencing, flow cytometry, and functional assays in Linc00673 knockout and wild-type mouse models treated with programmed death 1 (PD-1) blockade to dissect changes in immune landscape and tumor cell behavior. RESULTS: Linc00673 deletion enhanced the efficacy of PD-1 therapy, reducing tumor burden and prolonging survival. KO tumors showed increased infiltration of cytotoxic CD8⁺ T cells, reduced exhaustion, and improved antigen presentation. The tumor microenvironment shifted toward a pro-inflammatory state, with elevated dendritic cell function, reduced immunosuppressive macrophages, and improved T cell–tumor interactions. Linc00673 also promoted tumor cell migration and immune evasion independently of immune cells, suggesting dual tumor-intrinsic and -extrinsic roles. CONCLUSIONS: LINC00673 suppresses antitumor immunity and promotes tumor aggressiveness. Its deletion synergizes with PD-1 blockade, revealing a promising therapeutic target to overcome immune resistance in colorectal cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40364-025-00888-7.