Selected Articles from This Issue

While CD40 agonists enhance antitumor immunity via DC/T cell activation, their clinical use is limited by systemic immune toxicities, including cytokine release syndrome and hepatotoxicity. SHR-2005, an FcγR-dependent CD40 agonistic antibody, exerts robust CD40 signaling activation and potent T cell activation in vitro. The murine surrogate SHR-2005-mIgG1 shows potent antitumor effects in MC38 allograft following intravenous injection and enhances immune cell infiltration in bladder tissue upon intravesical instillation. Notably, SHR-2005 elicits lower IL-6 in human PBMCs, suggesting an improved safety profile. These findings nominate SHR-2005 as a promising intravesical therapy for high-risk NMIBC, offering therapeutic effects while minimizing systemic toxicity.TUB-040 is a novel, highly homogenous and hydrophilic DAR8 exatecan NaPi2b-targeting Antibody-drug conjugate built upon Tubulis’ ethynylphosphonamidate (P5) conjugation platform. The high stability and excellent biophysical properties of TUB-040 enabled by the P5 conjugation ensure efficient and sustained delivery of payload to tumor sites which translates into strong and durable in vivo efficacy in patient-derived xenografts, including models with low target expression. At the same time TUB-040 shows a highly favorable preclinical tolerability profile with no signs of lung toxicity. The data presented underline the therapeutic potential of TUB-040 to unlock NaPi2b as anti-cancer target and supported the advancement of TUB-040 into clinical phase I testing (NAPISTAR1-01; NCT06303505).Bromodomain protein TAF1 is the largest subunit of the TFIID transcription initiation complex. CRISPR and RNAi screens suggested TAF1 is a therapeutic target in certain tumors. However, small molecule inhibitors targeting the TAF1 bromodomain had no effect on tumor cells. The paper by Chen and colleagues shows that PROTAC molecules that promote TAF1 degradation induced apoptosis in acute myeloid leukemia cell lines and inhibited the growth of tumors in mice. The potent TAF1 degraders from this study can serve as chemical probes for investigating TAF1 transcription functions and the therapeutic potential of targeting TAF1 in cancer.Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with limited treatment options for advanced disease. Yagishita and colleagues evaluated farletuzumab ecteribulin (FZEC), an antibody-drug conjugate targeting folate receptor alpha (FRα), using 22 patient-derived xenograft models representing diverse EC subtypes. FZEC demonstrated dose-dependent antitumor effects, correlating with FRα expression. Notably, FZEC showed activity even in FRα-low or negative models. Intratumoral eribulin accumulation correlated more strongly with efficacy than FRα expression alone, suggesting both FRα-dependent and independent mechanisms. These findings support clinical development of FZEC for EC and highlight the complexity of ADC mechanisms of action.