<![CDATA[Background: Immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 benefit only 15%–30% of patients with solid malignancies, largely because of tumor immune microenvironment (TIME) resistance. Indonesian mangrove biodiversity remains an untapped source of multi-target small molecules. Objective: To assess the prognostic impact of the PD-L1/CTLA-4/LAG-3 checkpoint triad across human cancers and to identify mangrove phytoconstituents predicted to engage all three checkpoints. Methods: Pan-cancer immunogenomic profiling of 10,245 patients (33 TCGA cohorts) was integrated with digital cytometry (CIBERSORT-ABS, TIMER 2.0) and Tumor Immune Dysfunction and Exclusion (TIDE) modeling of CD274 (PD-L1), CTLA4 and LAG3. Reverse pharmacophore screening (PharmMapper) of 32 mangrove bioactives was followed by AutoDock Vina v1.2 docking (exhaustiveness 32) and NCI-60 CellMiner v2.9 analysis. Results: Triad co-expression independently predicted shorter overall survival, notably in hepatocellular carcinoma (HR = 1.84, 95% CI: 1.32–2.56, p < 0.001) and colorectal adenocarcinoma (HR = 1.62, 95% CI: 1.18–2.24, p = 0.004), and correlated with CD8+ T-cell exhaustion (r = −0.385), regulatory T-cell accumulation (r = +0.482) and M2 macrophage infiltration (r = +0.542; all p < 0.001). Screening prioritized 14 candidates. Avicennone C (Avicennia marina) bound the PD-L1 dimer interface (PDB: 6R3K; ΔG = −9.2 kcal/mol), betulinic acid (Sonneratia alba) the CTLA-4 MYPPPY loop (PDB: 1I8L; −8.7 kcal/mol) and rhizophin (Rhizophora mucronata) the LAG-3 D1 cleft (PDB: 7TZG; −8.4 kcal/mol). Baseline PD-L1 expression correlated with cytotoxic sensitivity across NCI-60 lines (r = +0.482, p = 0.002). Conclusion: Indonesian mangrove phytoconstituents are predicted to disrupt the PD-L1/CTLA-4/LAG-3 triad concurrently, providing a structural basis for the development of marine-derived cancer immunotherapeutics.]]>
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