Selected Articles from This Issue

A2A receptor is a major contributor to adenosine-mediated tumor promotion. However, response rates to A2A antagonists in cancer can be impacted by adenosine levels engaging another pro-tumorigenic adenosine receptor A2B. Here, Schiemann and colleagues have identified a novel dual A2A/A2B antagonist M1069, that shows stronger rescue of immune cell responses compared to A2A antagonist in adenosine-high settings in vitro and decreased growth of CD73-high/adenosine-high tumors in vivo. These findings suggest higher therapeutic potential for dual A2A/A2B antagonism over targeting of A2A alone in adenosine-rich TME, where A2B can play a complementary or compensatory role to A2A.HER2-targeted ADCs have shown impressive therapeutic potential in HER2-expressing solid tumors. Here, Satomaa and colleagues have developed a novel linker-payload for ADCs, mavg-MMAU, utilizing a stabilized glycopeptide linker and a hydrophilic auristatin glycoside payload. When conjugated to trastuzumab, the resulting antibody-drug conjugate had a wide therapeutic window with improvement in both in vivo efficacy and tolerability compared to standard auristatin ADCs. These findings encourage further exploration of mavg-MMAU based ADCs for cancer therapy.The replicative CMG (Cdc45-MCM-GINS) helicase is required for DNA replication and recovery from stalled forks. Oncogene-driven changes create MCM/CMG deficiencies, suggesting tumor cells will be sensitive to inhibitors of the CMG helicase. Here, Alexandrow and colleagues identified the first small molecule ATP-competitive inhibitors of the human CMG helicase (CMGi). We illustrate mechanisms by which CMGi bind and inhibit CMG ATP clefts, and show that CMGi block multiple ATP-dependent MCM/CMG processes in cells. Importantly, CMGi selectively reduce viability of mutant Ras-driven tumor cells. These CMGi provide a basis for drug discovery efforts aimed at developing novel CMGi with unique anti-cancer mechanisms.Small cell lung cancer (SCLC), constituting 15% of lung cancers, is an aggressive disease with limited treatment options. Recently, T cell bispecifics (TCB) have shown great promise in SCLC. Here, Dave and colleagues, characterise a novel TCB targeting the superbly SCLC-specific glycolipid, fucosyl-GM1. The TCB showed great target-dependent T cell activation and T cell mediated tumour killing in ex vivo assays, coinciding with potent in vivo SCLC killing. The anti-tumour impact was further enhanced by checkpoint inhibition, current SOC in ES-SCLC. These results support the ongoing development of the fucosyl-GM1 targeting TCB, representing an additional therapy option for SCLC patients.