Histone deacetylases (HDACs) play a critical role in epigenomic regulation of cancer cell signaling. HDAC inhibitors to-date have faced challenges due to poor isoform selectivity and narrow therapeutic indices. In this first disclosure, Diamond and colleagues report the discovery and preclinical development of the novel, orally bioavailable, class I-targeting HDAC inhibitor, OKI-179 (NCT03931681). OKI-179 was active against solid tumors in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. OKI-179 is a promising next generation HDAC inhibitor suitable for combining with other targeted agents based on its potency, desirable class I HDAC inhibition profile and oral bioavailability.Most men on androgen deprivation therapy (ADT) with advanced hormone-sensitive prostate cancer (HSPC) will develop castration resistant prostate cancer (CRPC), a lethal form of prostate cancer (PC). Previously, our group has demonstrated that IKKε is overexpressed in CRPC and its expression is directly correlated with aggressive PC in patients. In this issue, Gilbert and colleagues demonstrate that IKKε inhibitors, BX795 and Amlexanox, specifically target androgen-independent PC to induce a senescent phenotype, DNA damage and genomic instability. Our in vivo study shows that androgen-independent tumor PC growth is delayed with IKKε inhibitors, providing additional effective therapeutic strategies in the management of patients with CRPC.HLRCC is notorious for being resistance to all tested therapies. A standardized treatment modality for this aggressive subtype of renal tumor is still lacking. In this issue, Kerimoglu and co-workers showed that a combination of two clinically well tolerated therapeutics, rapamycin and Cyst(e)inase®, is efficacious in suppressing HLRCC growth in vivo. The combination induces ferroptosis in tumor tissues with no observable systemic toxicity. Given that rapamycin is an FDA-approved drug, and cyst(e)inase is currently in clinical trial, the combination provides an opportunity to translate into a HLRCC treatment strategy.Pediatric osteosarcoma is an aggressive bone tumor with a poor prognostic for those patients with metastatic disease or those who do not respond to therapy. Oncolytic viruses have shown a safe toxicity profile and are becoming a real treatment option for pediatric solid tumors. In this issue, Martinez-Velez and colleagues demonstrated the therapeutic effect of Delta-24-ACT, an oncolytic adenovirus armed with the 4-1BB ligand, in local and metastatic murine osteosarcoma models. Their data show the ability of Delta-24-ACT to turn the osteosarcoma tumor microenvironment from cold to hot, underscoring its potential as a therapeutic for this disease.