Selected Articles from This Issue

TIGIT and PVRIG are two receptors on T and natural killer (NK) cells and have been demonstrated to suppress the activation of immune cells. Here, Lin and colleagues present the development and characterization of the bispecific antibody blocking both TIGIT and PVRIG (SHR-2002), first of its kind to enter clinical trials worldwide. SHR-2002 activated T and NK cells and demonstrated enhanced anti-tumor activity compared to monotherapies and synergies with anti-PD-1/PD-L1 antibodies. SHR-2002 also demonstrated favorable pharmacokinetics and safety profile in non-human primates. These data support further clinical investigation of SHR-2002 in multiple cancers.USP1 has been identified as a synthetic lethal target in BRCA1/2-mutated cancers, offering potential for therapeutic intervention in homologous recombination-deficient (HRD) cancers. Here, Simoneau and colleagues have characterized a potent and selective USP1 inhibitor, TNG348, utilizing CRISPR screens to uncover cellular pathways mediating its anti-cancer activity. TNG348 was shown to synergize with PARP inhibitors (PARPi), driving growth inhibition in HRD tumors, including those sensitive to PARPi and with acquired resistance. While clinical development of TNG348 was discontinued due to grade 3/4 liver function abnormalities in patients, the authors present significant mechanistic studies that support the continued exploration of USP1 inhibitors in combination with PARPi for HRD cancer treatment.Mesothelioma cells frequently exhibit Hippo signaling pathway alteration; thus, activated TEAD transcription factors cause cancer-promoting gene over-expression. TEAD inhibitors are expected to be effective against mesothelioma; however, the detailed mechanisms remain unclear. Akao and colleagues, showed that the small molecule, K-975, is a pan-TEAD inhibitor that acts cytostatically on mesothelioma cells. Mesothelioma cells that exhibited resistance despite the inactivation of the Hippo signaling pathway showed activation of MYC signaling. This study provides valuable insights into therapeutic strategies for mesothelioma using TEAD inhibitors currently under development.Anaplastic thyroid cancer (ATC) is a rare but dire disease, with five-year survival rates of <10%. UU-40, a full-size antibody developed by the authors of this study, targets the cancer-associated cell-surface antigen CD44v6, with excellent affinity. The current study evaluates the expression of CD44v6 in ATC and the feasibility of utilizing UU-40 labeled with Lutetium-177 (177Lu) for molecular radiotherapy of ATC. Immunohistochemistry and in vitro studies indicate that CD44v6 is expressed in ATC and in vivo therapy studies using 177Lu-UU-40 demonstrated excellent efficacy. These data warrant further studies for future clinical development of UU-40 for molecular radiotherapy against CD44v6-positive cancers.