Naked cuticle homolog 1 (NKD1) peptide presented by Human leukocyte antigen A*02:01 (HLA-A*02:01) (NKD1-HLA-A2)

NKD1-derived peptide presented by HLA-A2 is a novel peptide-major histocompatibility complex (pMHC) target for cancer immunotherapy, specifically for microsatellite stable (MSS) metastatic colorectal cancer (mCRC) (MSKCC, 2024; AACR, 2026). The target protein, Naked cuticle homolog 1 (NKD1), is an oncofetal protein that acts as a negative regulator of the canonical Wnt/beta-catenin signaling pathway (NIH, 2026; PubMed, 2013). While NKD1 expression is typically restricted to fetal development and absent in healthy adult tissues, it is frequently re-expressed in colorectal cancer cells that have reactivated the fetal Wnt developmental program, often driven by APC mutations (MSKCC, 2024; AACR, 2026). The presentation of specific NKD1-derived peptides, such as the nonamer SLLHTIYEV, by the HLA-A*02:01 allele creates a highly tumor-specific epitope on the cell surface (Google Patents, 2026). Therapeutic strategies targeting this complex include engineered T-cell receptor (TCR) therapies and TCR-mimetic bispecific molecules, which aim to provide a precision treatment option for the approximately 34% of MSS mCRC patients who are HLA-A2 positive (MSKCC, 2024). This target is particularly significant as it addresses a major unmet need in colorectal cancer, where traditional checkpoint inhibitors have shown limited efficacy (AACR, 2026). Current lead candidates, such as the NKD1-specific TCR-T cell therapy developed by investigators at Memorial Sloan Kettering Cancer Center, have demonstrated potent cytotoxic activity against patient-derived organoids while maintaining a favorable safety profile in preclinical models (MSKCC, 2024; AACR, 2026).

Other names

NKD1-A2 complexNKD1-derived peptide-MHC complexSLLHTIYEV-HLA-A*02:01NKD1-HLA-A2

Engineered T-cell receptors (TCRs) or TCR-mimetic antibodies recognize the specific NKD1 peptide-HLA-A2 complex on the surface of cancer cells, leading to T-cell activation, inflammatory cytokine production, and targeted tumor cell lysis.