Enzymatic and Bioengineered Vulnerabilities Offer Routes to Re-sensitize Resistant Tumors

Dual PDIA1/PDIA5 blockade undermines AR stability and an engineered anti-αvβ3 antibody reprograms macrophages to kill αvβ3+ tumors — both approaches point to biomarker‑driven re‑sensitization strategies for patients with AR‑driven prostate cancer and for αvβ3‑high tumors, and they warrant prioritization in translational pipelines that emphasize selection and pharmacodynamic readouts.

Patient-derived samples and PDX/mouse models show that combined inhibition of PDIA1 and PDIA5 reduces AR protein levels and tumor cell viability while enhancing responses to enzalutamide, with measurable tumor regressions in treated PDXs. Mechanistically, dual PDIA blockade promotes AR degradation, generates proteotoxic and mitochondrial injury signatures, and elevates oxidative stress markers that together reduce tumor fitness. Consequently, the preclinical program reports robust increases in AR‑targeted drug sensitivity and substantive tumor control when PDIA co‑inhibition pairs with standard AR blockade. The PDIA1/PDIA5 study links these effects to AR proteostasis perturbation and highlights candidate PD biomarkers — reduced AR stability, proteotoxic stress readouts and mitochondrial injury markers — that could serve for patient selection and target‑engagement monitoring.

Macrophage‑engaging antibody engineering using an anti‑αvβ3 scaffold induces iNOS expression in tumor‑associated macrophages and mediates direct killing of αvβ3+ tumor cells in ex vivo patient tissues and multiple mouse tumor models. Importantly, efficacy is macrophage dependent and is lost with macrophage depletion, demonstrating that the mechanism requires innate‑immune effector engagement across lung, pancreatic and prostate αvβ3‑enriched contexts. Moreover, tumor αvβ3 expression by IHC or receptor‑level assays and macrophage abundance or activation state emerge as practical companion biomarkers to identify and stratify responsive cases. The engineered anti-αvβ3 antibody report documents antibody optimization that maximizes macrophage engagement and iNOS‑mediated tumor cell killing across αvβ3‑high models.