Partitioned Literature Aggregation and Transcriptomic Survival Analysis Identify an Immune-Contextualized Four-Gene mTOR Prognostic Composite in Hepatocellular Carcinoma

Background: Clinical responses to first-generation mechanistic target of rapamycin (mTOR) inhibitors vary substantially across malignancies, indicating that pathway activation alone is insufficient to identify tumors likely to depend on mTOR signaling. Methods: We developed Partitioned Literature Aggregation (PLA), a framework that organizes large biomedical literature collections into disease-specific summaries before cross-disease aggregation. A single discovery query identified malignancies evaluated with rapamycin, everolimus, or temsirolimus, after which each disease-specific corpus was independently interrogated using an identical standardized prompt. Applied to more than 4.4 million PubMed abstract records representing 24 disease-specific corpora, PLA generated comparative clinical summaries that identified renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) as contrasting anchors of established and unsuccessful rapalog development, respectively. To investigate molecular features associated with this clinical contrast, overall-survival relationships for mTOR-associated genes were evaluated across publicly available transcriptomic cohorts using the Kaplan–Meier Plotter platform. Associations meeting the prespecified exploratory threshold of p < 0.01 were assembled into a gene-by-indication matrix according to hazard-ratio direction. Results: HCC and RCC exhibited distinct prognostic architectures, supporting further investigation of the HCC state associated with historically limited rapalog efficacy. Within HCC, stepwise composite analysis identified a four-gene prognostic signature comprising PPARGC1A, EIF4E, RRAGC, and FKBP1A. Higher four-gene adverse-risk scores were associated with poorer overall survival (HR for high versus low score, 2.59; 95% CI, 1.8–3.74; log-rank p = 1.1 × 10−7). The complete four-gene architecture was not uniformly retained across immune contexts. Exploratory subgroup analyses identified significant prognostic associations in eight TLR-high strata after correction for multiple comparisons, whereas none of the TLR-low strata met the corrected threshold. Component-gene associations were also observed in seven tumor-microenvironment strata—MSC-low, CD4-low, RegT-high, Th1-high, NK-high, macrophage-high, and CD8-low. These exploratory observations generate hypotheses concerning immune context. Conclusions: These findings link the prognostic signature to immune context and support prospective testing of its potential to identify HCC patients who benefit from mTOR-directed therapy.