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Background MCC and SCLC remain among the most treatment-refractory solid tumors despite first-line ICB, with durable responses in <25% of patients. Loss of HLA-I antigen presentation represents a common immune-escape route in MCC. MDK, a heparin-binding growth factor that is over-expressed in many cancers and dampens IFN signalling and DC maturation, is highly transcribed in MCC and SCLC tumors and lines, yet its contribution to neuroendocrine ICB failure is undefined.Methods Using CRISPR/Cas9 we generated isogenic MDK-KO human MCC (WaGa, MKL-1) and SCLC (NCI-H69, NCI-H82) models. Bulk RNA-seq, phospho-proteomics, flow cytometry, and monocyte-derived DC co-cultures quantified IFN responsiveness, antigen-presentation machinery, and DC activation. Public bulk- and single-cell RNA-seq datasets (102 MCC, 70 SCLC) were mined for MDK-immune correlations.Results MDK deletion restored type I/II IFN signalling, re-engaging STAT1/IRF1 networks and driving 4– to 9-fold up-regulation of HLA-A/B/C surface levels across all lines (P < 0.01). MDK-KO tumors re-sensitized to low-dose IFN-γ, yielding >300 differentially up-regulated inflammatory transcripts, including TAP1/2 and CXCL9/10. Co-culture with MDK-KO cells elicited a two-fold increase in CD86^hi HLA-DR^hi DCs versus wild-type (WT) controls, consistent with prior evidence that MDK restrains DC maturation Patient-omics analyses confirmed an inverse correlation between MDK expression and IFN-stimulated, antigen-processing, and cytotoxic-lymphocyte signatures (Spearman ρ = –0.61 to –0.44; FDR < 0.001). High-MDK tumors were enriched in transcriptionally defined ‘immune-cold’ neuroendocrine subtypes and associated with early ICB progressionConclusions MDK functions as a nodal suppressor of IFN-driven anti-tumor immunity in MCC and SCLC, simultaneously curbing tumor-intrinsic antigen presentation and extrinsic DC activation. Genetic or pharmacologic MDK blockade may synergize with ICB to convert immune-cold neuroendocrine tumors into responsive disease.Ethics Approval We obtain de-identified human surgical samples through the Yale Spore in Skin Cancer (IRB protocol # 0609001869). The Spore systematically informs and provides the opportunity for all patients treated for any skin cancer, including women and minorities (including special focus on translated consent documents/processes for the substantial international patient population in Connecticut). Patient/sample relevant clinical characteristics are provided upon request by the Spore, and we operate with only a de-identified sample ID, to avoid any risk to patient privacy. All testing including sequencing is approved via the IRB approved consent.