OX40 (TNFRSF4) Tracks Immune Infiltration in Small Cell Lung Cancer and Shows a Cohort-Specific, Non-Replicated Association with the POU2F3/SCLC-P Subtype: A Multi-Source in Silico Analysis

OX40 (TNFRSF4) is a costimulatory T-cell receptor and OX40 agonists are in clinical development, yet its role in small cell lung cancer (SCLC) is still to be characterised. We analysed the discovery cohort (n = 77, 48 events), GSE60052 (n = 79 tumours; 48 with survival), GDSC1+GDSC2 (61 SCLC cell lines, 542 drugs) and human SCLC single-cell atlas (77,143 cells from primary and metastatic sites, 20 donors), using Cox models, FDR-controlled correlation, nested-model comparison and deconvolution. High TNFRSF4 showed a non-significant protective trend (pooled HR = 0.86 per SD, 0.68–1.10, p = 0.23); a nominal cutpoint did not survive correction for cutpoint search (p = 0.25). No drug reached FDR < 0.05 among 658 tests, including platinum agents and etoposide. TNFRSF4 tracked immune infiltration (13-gene score ρ = 0.76, p = 3 × 10−16) and was detected in 17.6% of T cells versus 1.03% of malignant cells in all 20 donors. OX40 was enriched in the POU2F3/SCLC-P subtype (p = 0.033), persisting after immune adjustment (β = 1.32, p = 0.011) but not replicating independently (p = 0.10). Adding TNFRSF4 to clinical-plus-immune models provided no meaningful discrimination gain (ΔC-index ≤ 0.005). Power was limited to HR ≥ 1.50 harmful or HR ≤ 0.67 protective, so the observed trend is undetectable at this size. Bulk OX40 therefore primarily reflects immune infiltration, and its SCLC-P association is a hypothesis for prospective testing.