Cellular & molecular immunologyOct 13, 2026

Activating an alternative NF-κB pathway to improve cancer-killing by engineered T cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 15, 2026

Abstract

Overexpression of p52 in TCR-based T cells enhances their persistence and tumor control.

The noncanonical NF-κB axis was identified as a key regulator of T cell persistence in STAR-T cells.
RELB overexpression led to dose-dependent cytotoxicity, prompting the investigation of p52 as a safer alternative.
p52 overexpression sustained T cell proliferation and preserved effector functions under prolonged antigen exposure.
Increased intratumoral trafficking potential was observed, particularly in CD8+ T cells, contributing to improved tumor control.
Transcriptomic profiling showed upregulation of cell cycle programs and chemokine receptors while downregulating apoptosis and exhaustion-related genes.
p52 overexpression restored RELB nuclear translocation in the presence of PD-1/PD-L1 interaction, suggesting enhanced resistance to checkpoint-mediated suppression.

Simplified

Engineering autologous T cells for adoptive therapies has revolutionized cancer treatment, yet limited persistence remains a major barrier to robust clinical responses and durable disease control. Although costimulation with 4-1BB markedly improves CAR-T-cell persistence, no comparably effective approach has been identified to enhance persistence in T-cell therapies that rely on native TCR signaling, including conventional TCR-T cells and synthetic T-cell receptor and antigen receptor (STAR) T cells. To identify intrinsic persistence regulators in a TCR-based context, we performed an in vivo CRISPR activation screen in STAR-T cells and identified the noncanonical NF-κB axis, with RELB as the top hit. Direct RELB overexpression, however, exhibited dose-dependent cytotoxicity, motivating a translational alternative: overexpression of p52, the ncNF-κB transcription partner of RELB. Under prolonged antigen exposure, p52 overexpression sustained proliferation, preserved effector functions, and increased the intratumoral trafficking potential, particularly in CD8⁺ T cells, thereby yielding superior tumor control. Mechanistically, transcriptomic profiling revealed coordinated upregulation of cell cycle programs and chemokine receptors, along with downregulation of apoptosis and exhaustion-associated modules. Moreover, p52 overexpression restored RELB nuclear translocation in the context of PD-1/PD-L1 engagement, indicating partial resistance to checkpoint-mediated suppression and sustained ncNF-κB activity in PD-L1^hi immunosuppressive environments. Collectively, our findings identify p52 as an antigen-dependent enhancer of ncNF-κB, conferring durable persistence and checkpoint resilience on TCR-based T cells and providing a feasible strategy to improve therapeutic effects in solid tumors.

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Activating an alternative NF-κB pathway to improve cancer-killing by engineered T cells

Abstract

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