Cancer cells are prone to cytosolic DNA accumulation. The authors demonstrate that the exonuclease TREX1, which degrades endogenous cytosolic DNA, is a key innate immune checkpoint limiting tumor immunogenicity and a potential target for cancer immunotherapy.

It is unclear how chromosomally unstable cancer cells avoid immune responses from cGAS-STING detection of cytosolic DNA. The authors show that TREX1 nuclease upregulation guards against antitumor immune responses by degrading cytosolic DNA and limiting cGAS-STING–dependent interferon signaling.

Therapeutic usage of cytokines in patients is limited by toxicity. The authors report that blocking a cytokine binding protein, IL18BP, to enhance the cytokine’s natural activity yields antitumor activity in preclinical models and shows promise for clinical translation.

This first-in-human, randomized trial demonstrates that combining radium-223 with pembrolizumab does not significantly impact the tumor microenvironment in patients with metastatic castration-resistant prostate cancer. Data highlight that upregulation of immune checkpoint molecules could impede the combination’s clinical efficacy.

This study demonstrates that a CD3/CD137 dual-specific Fab, generated through mutagenesis of a conventional CD3 antibody, improves the efficacy of DLL3-targeted T-cell engagers, suggesting that engineering of the CD3 binding region can unlock the potential of T-cell engagers.

There is interest in harnessing NK cells to generate allogeneic cell therapies. The authors report IND-enabling studies testing the safety and efficacy of engineered PD-L1⁺ NK cells expressing soluble IL15, and supporting a clinical trial for NSCLC.

DHA has direct growth suppressing effects on tumour cells. The authors show it also has an immunomodulatory effect, limiting tumour growth by enhancing NK-cell IFNγ production and cytotoxicity, likely by upregulating mitochondrial activity via the PGC-1α pathway.

Identifying immunogenic cancer neoantigens for cancer vaccine design is challenging. The authors uncover NOPs as a widespread source of neoantigens derived from structural genomic variants and indels. The findings open new avenues towards personalized immunotherapies for cancer.

Tumor cell–intrinsic IRF1 was recently shown to promote tumor growth. The authors show that tumor cell–specific targeting of IRF1 through IRF2 expression can suppress tumor growth in a model of melanoma, suggesting a novel immunotherapeutic approach.