Journal of genetics and genomics = Yi chuan xue baoNov 2, 2026

Triggering death receptor 5 makes cancer cells more vulnerable to attack by natural killer and T cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Nov 3, 2026

Abstract

CFLAR depletion sensitizes cancer cells to NK- and T-cell attack in vitro and in vivo.

CFLAR encodes cFLIP, which suppresses death-receptor signaling and impairs cytotoxicity of immune cells.
High expression of CFLAR is linked to reduced lymphocyte infiltration and poorer responses to immune checkpoint blockade.
Inflammation induced by immune effector cells increases expression of CFLAR and death receptor 5 (DR5) via p38-MAPK signaling.
The DR5 agonist conatumumab enhances lymphocyte-mediated killing and improves responses to various cancer therapies.
Combining DR5 agonism with NKG2A blockade enhances NK- and T-cell responses and may overcome resistance to anti-PD-1 therapy.

Simplified

Immunotherapy has revolutionized cancer care, yet resistance frequently undermines its efficacy. Although tumor-intrinsic resistance pathways have been mapped, how immune pressure regulates death-receptor vulnerability and anti-apoptotic buffering remains less defined. Using genome-wide CRISPR-Cas9 screening in cancer cells co-cultured with natural killer (NK) cells, we identify CFLAR, encoding cFLIP, as a dominant suppressor of death-receptor signaling that impairs NK- and T-cell cytotoxicity. CFLAR depletion sensitizes cancer cells to NK- and T-cell attack in vitro and in vivo. Single-cell and spatial transcriptomic analyses link high CFLAR expression to reduced lymphocyte infiltration and poorer responses to immune checkpoint blockade. Mechanistically, immune effector cell-induced inflammation increases CFLAR and death receptor 5 (DR5) expression in association with p38-MAPK signaling, balancing survival and death under immune pressure. The DR5 agonist conatumumab enhances lymphocyte-mediated killing and improves responses to cellular therapies, checkpoint blockade, and chemo-immunotherapy. Combining DR5 agonism with NKG2A blockade co-activates NK- and T-cell responses and overcomes anti-PD-1 resistance in MHC-I-deficient tumors. These findings identify the DR5-cFLIP axis as an immune-pressure-associated, pharmacologically targetable vulnerability and support rational combinations of DR5 agonists with multiple immunotherapies for refractory cancers.

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Triggering death receptor 5 makes cancer cells more vulnerable to attack by natural killer and T cells

Abstract

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