DKK1-CKAP4 axis functions as an immunometabolic checkpoint linking tumor-intrinsic signaling with immune suppression

The Dickkopf (DKK) proteins, particularly DKK1, along with their receptor cytoskeleton-associated protein 4 (CKAP4), play crucial roles in the pathogenesis and progression of gastrointestinal (GI) cancers. The DKK1-CKAP4 axis activates the phosphoinositide 3-kinase/ protein kinase B (PI3K–AKT) signaling pathway, thereby promoting the proliferation, migration, and invasion of cancer cells. Simultaneously, this axis modulates the tumor immune microenvironment (TME) by influencing the recruitment and activity of various immune cells, such as tumor-associated macrophages, regulatory T cells, and cytotoxic T cells. The co-expression of DKK1 and CKAP4 is associated with poor prognosis in several GI malignancies, including esophageal, gastric, pancreatic, colorectal, and liver cancers. Preclinical studies have demonstrated that targeting the DKK1-CKAP4 axis using humanized antibodies or small molecule inhibitors can inhibit tumor growth, enhance cytotoxic immune cell infiltration, and improve responses to chemotherapy and immunotherapy. Early clinical trials evaluating anti-DKK1 therapies have yielded mixed results; however, studies enriched with DKK1-high patients have demonstrated encouraging efficacy, underscoring the critical importance of biomarker-driven patient selection. DKK1 expression has also emerged as a potential predictive biomarker for response to these therapies. Further investigation into optimal combination regimens and patient selection strategies is warranted to fully harness the therapeutic potential of targeting the DKK1-CKAP4 axis in GI malignancies. Modulating this immunomodulatory pathway represents a promising approach to overcome immunosuppression, enhance the efficacy of current immunotherapies, and improve the outcomes of patients with GI cancers.