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Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition
Nam M. et al.
Nat Metab. 2024
Pyrimidines, key components of DNA and RNA, are vital for nucleic acid synthesis in rapidly proliferating tumor cells. Cancer cells, facing nutrient scarcity due to poor vascularization, adapt metabolically to sustain proliferation. This study investigates how glucose limitation in the tumor microenvironment affects cancer therapy targeting pyrimidine biosynthesis.
First, the researchers performed CRISPR-based screens to identify metabolic pathways influenced by glucose restriction. They discovered that low glucose levels protect cancer cells from the effects of pyrimidine biosynthesis inhibitors like brequinar (BQ) and PALA. Mechanistically, low glucose reduces UDP-glucose synthesis, preserving pyrimidine availability, and delays replication fork stalling. Additionally, low glucose inhibits apoptosis by suppressing mitochondrial outer membrane permeabilization, reducing caspase-9 activation. These findings were validated in multiple cell lines, showing that glucose scarcity selectively supports cancer cell survival under pyrimidine synthesis inhibition.
Next, they examined replication stress and apoptosis under pyrimidine-depleted conditions. Low glucose mitigated DNA damage and replication fork stalling induced by pyrimidine inhibitors. DNA fiber assays confirmed that nucleotide incorporation at replication forks continued under low glucose. Furthermore, glucose limitation did not similarly protect against purine synthesis inhibition, indicating a specific effect on pyrimidine metabolism.
This research underscores the critical impact of tumor nutrient environments on chemotherapy efficacy. Understanding these metabolic adaptations may guide strategies to enhance cancer therapies targeting nucleotide biosynthesis pathways.
DOI: 10.1038/s42255-024-01166-w
02
Cai. et al.
Nat Biomed Eng. 2024
The regulation of immune responses within the tumor microenvironment (TME) is crucial for advanced cancer therapies. While anti-4-1BB agonist antibodies stimulate CD8+ T cells, their toxicity limits clinical use. This study presents an engineered fusion protein combining anti-4-1BB with interleukin-15 (IL-15), linked by a tumor protease-sensitive peptide, to achieve concurrent depletion of regulatory T (Treg) cells and activation of cytotoxic T lymphocytes (CTLs).
First, the researchers designed a cleavable anti-4-1BB–IL-15 fusion protein to specifically target the TME. Preclinical models demonstrated that the protein significantly reduced Treg cells within tumors while expanding tumor-specific CTLs without affecting peripheral tissues. This strategy enhanced antitumor responses and minimized systemic toxicity compared to separate administration of anti-4-1BB and IL-15.
Next, they evaluated the protein in mouse cancer models, revealing superior tumor control and reduced adverse effects. Single-cell RNA sequencing confirmed the protein’s ability to restore CD8+ T cell functionality by reducing exhaustion markers. Importantly, the protease-sensitive linker allowed precise IL-15 release in the TME, avoiding peripheral immune cell activation, which commonly leads to toxicity.
This study introduces a promising therapeutic approach that combines immune modulation and localized cytokine delivery. By addressing key challenges in cancer immunotherapy, it provides a blueprint for developing safer, more effective treatments for advanced cancers.
DOI: 10.1038/s41551-024-01303-6
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