Transcriptomic Integration Reveals a Conserved Inflammatory--Proliferative Paradox in Acquired Resistance to Immune Checkpoint Blockade

Acquired resistance to immune checkpoint blockade (ICB) is increasingly recognized as an active adaptive process. However, prior studies have typically focused on individual tumor models, limiting the ability to distinguish conserved mechanisms from model-specific observations. Here, we integrated four independent transcriptomic datasets of acquired ICB resistance, spanning human non-small cell lung cancer (NSCLC) biopsies, murine CT26 colorectal tumors, organoid-derived murine NSCLC tumors, and EMT6 breast cancer cells. Differential expression analysis was performed within each dataset, followed by an intersection-based consensus approach to identify reproducible resistance-associated programs. Contrary to the conventional cold tumor paradigm, acquired-resistance tumors consistently maintained interferon-{gamma} response and innate immune signaling while simultaneously activating cell-cycle programs and constitutive KRAS signaling signatures across all four models. We term this an apparent inflammatory-proliferative paradox: the persistence of IFN-{gamma}-driven inflammatory signatures, canonically associated with productive antitumor immunity, in tumors that have escaped immune control. Notably, this program was retained in immune-depleted organoid and cell-line models, supporting a tumor-cell-associated component maintained independently of the immediate immune microenvironment. Transcription factor activity inference identified a conserved regulatory backbone linking interferon-associated regulators (STAT2, IRF2) with proliferation drivers (E2F4, TFDP1) and suppression of lineage-specifying factors (HNF4A, EGR1). Integrated network analysis resolved these signals into three reinforcing modules, namely hyper-proliferative outgrowth, active inflammatory adaptation, and lineage identity loss. This architecture provides a systems-level framework for prioritizing combination strategies that simultaneously address interconnected resistance axes.