NKAP overexpression promotes gastric cancer immune escape by inducing IL-10 secretion from mature dendritic cells during anti-PD-L1 therapy.

Background: Gastric cancer (GC) remains a major clinical challenge due to its high mortality and propensity for immune escape, which critically limits the efficacy of immunotherapy. The immunosuppressive tumor microenvironment (TME) is a key factor restricting the effectiveness of immune checkpoint inhibitors (ICIs) in GC. The nuclear factor kappa B (NF-κB) activating protein (NKAP), a conserved regulator of the NF-κB pathway, has been shown to drive immune evasion in other cancer types by modulating cytokine networks and immune cell functions. However, the specific role and mechanisms of NKAP in shaping the immunosuppressive TME of GC and contributing to resistance against programmed death ligand 1 (PD-L1) blockade therapy remain largely unexplored. Therefore, this study aimed to investigate the role of NKAP in the GC TME and elucidate its mechanisms in driving immune escape and resistance to anti-PD-L1 therapy.

Methods: We analyzed datasets from The Cancer Genome Atlas (TCGA) datasets and clinical specimens from patients with GC who received neoadjuvant therapy with PD-L1 inhibitors to evaluate NKAP expression and its association with clinicopathological features. In vitro models of mature dendritic cells (mDCs) and murine xenografts were used to investigate the mechanism underlying NKAP's involvement. NF-κB pathway activation, interleukin-10 (IL-10) secretion, and regulatory T cell (Treg) differentiation were assessed via luciferase assays, enzyme-linked immunosorbent assay, and flow cytometry. Changes in the TME and the therapeutic efficacy of PD-L1 blockade were evaluated in xenograft models.

Results: Elevated NKAP expression correlated with advanced tumor-node-metastasis (TNM) stage, lymph node metastasis, and poor tumor differentiation in patients with GC. High NKAP levels predicted higher residual tumor burden post-PD-L1 therapy. Mechanistically, NKAP overexpression activated the NF-κB pathway in mDCs, driving IL-10 secretion and promoting naïve T-cell differentiation into immunosuppressive Tregs. This process fostered an immunosuppressive TME, which diminished the efficacy of PD-L1 blockade in murine models.

Conclusions: NKAP is a critical regulator of GC immune escape, linking NF-κB-driven IL-10 production in mDCs to Treg-mediated immunosuppression during anti-PD-L1 therapy. Targeting NKAP may reverse resistance to ICIs, offering a promising strategy for improving clinical outcomes in patients with GC.