Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response

Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti–PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy. Colorectal cancer (CRC) is characterized by substantial genetic and epigenetic heterogeneity, underscoring the need for novel therapeutic targets. While immunotherapy has led to significant advancements in cancer treatment, approximately 85% of CRC patients exhibit resistance due to different genetic and epigenetic features. Multi-omics approaches, which integrate data across genomic, proteomic, and metabolomic layers, have emerged as powerful tools for elucidating disease mechanisms. In this study, we conducted multi-omics analyses on tumor and adjacent normal tissues from 13 CRC patients. Complementary in vitro and in vivo experiments demonstrated that lncRNA 60967.1 regulates the PLCD4/ATRA axis and modulates the immune response to anti-PD-1 therapy, thereby promoting CRC progression. Our findings reveal a novel regulatory network involving lncRNA, PLCD4, and ATRA, providing a potential new target for CRC therapy.