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CISH, a key intracellular checkpoint, in comparison and combination to existing and emerging cancer immune
Florencia Cano1, Alberto Bravo-Blas1, Mathilde Colombe1
1Intima Bioscience, New York, NY, USA.
Abstract:
Over the past decade, Immuno-Oncology has largely focused on blocking inhibitory surface receptors like PD-1 to enhance T cell anti-tumor activity. However, intracellular immune checkpoints such as CISH, which function independently of tumor-expressed ligands, offer powerful and previously untapped therapeutic potential. As a downstream regulator of TCR signaling, CISH controls T cell activation, expansion, and neoantigen reactivity. Though historically considered undruggable, recent advances in CRISPR engineering have enabled functional interrogation of these targets. We demonstrate that CISH deletion enhances T cell activation and anti-cancer functions more effectively than other emerging intracellular checkpoints. In CAR-T cells, CISH inactivation significantly increased sensitivity to tumor antigen, enabling robust recognition and killing even at low antigen levels, conditions that often lead to treatment failure with conventional T cell therapies, mirroring antigen escape scenarios seen in solid tumors. Our findings further validate CISH as a potent and druggable intracellular checkpoint capable of boosting anti-tumor T cell responses across diverse cancer types, independent of PD-L1 status. The underlying mechanisms of CISH inhibition may help explain the positive outcomes reported in recent clinical studies of this approach in solid tumor immunotherapy.
Insights
Targeting the intracellular immune checkpoint CISH enhances T cell anti-cancer functions and CAR-T cell sensitivity to tumor antigens, offering new therapeutic potential beyond PD-1 blockade.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Immuno-Oncology traditionally targets surface receptors like PD-1.
- Intracellular immune checkpoints, such as CISH, represent a novel therapeutic avenue.
- CISH regulates T cell receptor signaling, impacting T cell activation and anti-tumor responses.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the intracellular immune checkpoint CISH.
- To evaluate the efficacy of CISH deletion in enhancing T cell anti-tumor functions.
- To assess the impact of CISH inactivation on CAR-T cell sensitivity and efficacy.
Main Methods:
- CRISPR engineering for functional interrogation of CISH.
- Assessment of T cell activation and anti-cancer functions following CISH deletion.
- Evaluation of CAR-T cell sensitivity to varying tumor antigen levels after CISH inactivation.
Main Results:
- CISH deletion significantly enhanced T cell activation and anti-cancer functions compared to other checkpoints.
- CISH inactivation in CAR-T cells increased tumor antigen sensitivity, improving killing at low antigen levels.
- These effects were observed independently of PD-L1 status, suggesting broad applicability.
Conclusions:
- CISH is a druggable intracellular checkpoint that potently boosts T cell anti-tumor responses.
- Targeting CISH offers a promising strategy for enhancing immunotherapy across diverse cancer types.
- CISH inhibition mechanisms may explain recent clinical successes in solid tumor immunotherapy.
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