Volume 4 Issue 3, March 2023

Although targeting cancer cells on the basis of tissue-specific expression of key factors is an important strategy in precision oncology, few such therapies exist. Chemical screening now identifies YC-1 as a tissue-specific anti-cancer compound that is activated in the liver by the sulfotransferase enzyme SULT1A1.

Transactivation hubs and related biomolecular condensates are emerging as relevant molecular players in cancer biology. A new study now links PD-L1 upregulation on the cancer cell surface and IRF1–KAT8 transactivation hubs at PD-L1 loci. Therapeutic targeting of these hubs holds potential to unleash antitumor immunity.

High-fat diet and the secretome of breast tumors prime distant organs for metastasis formation. During lung priming, alveolar type II cells increase the release of palmitate, which is oxidized to acetyl-CoA by metastasizing breast cancer cells, where the increased acetylation of the NF-κB subunit p65 activates a pro-metastatic transcriptional program.

Speiser and colleagues review the latest advances in understanding of the biological roles of CD4⁺ T cells in cancer immunology and applications for immunotherapy.

Shaw and colleagues discuss the oncogenic roles of ALK in lung cancer, targeting approaches and the mechanisms underlying acquired resistance to ALK-directed therapy.

Fendt and colleagues find that pre-metastatic niche formation and a high-fat diet increase palmitate availability in future organs of metastases and show that breast cancer cells use palmitate to generate acetyl-CoA, acetylate the NF-κB subunit p65 and induce pro-metastatic signaling.

Shi et al. report a sulfonation-dependent vulnerability of liver tumors expressing the sulfotransferase SULT1A1 by showing their sensitivity to the small molecule YC-1 and identifying structurally related compounds that can be modified by SULT1A1.

Wu et al. report that IFNγ induces the phase separation of KAT8 and IRF1 into condensates that promote PD-L1 upregulation. They further identify a peptide that blocks KAT8–IRF1 condensates, reducing PD-L1 levels and increasing antitumor immunity.

Adler et al. identify granulocyte-derived lipocalin-2 as a mediator of inflammatory astrocyte activation, which in turn facilitates brain metastasis in breast cancer and melanoma.

Park et al. show that in the process of metastasis, dying tumor cells enhance the outgrowth of their surviving counterparts via nuclear expulsion, resulting in an extracellular DNA–protein complex that activates RAGE receptors on tumor cells.