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Further stimulating a lysosomal Zn 2+ release channel selectively kills metastatic melanoma cells.

CXCL10 signaling prevents, rather than promotes, progression of premalignant pancreatic neoplasia.

Immunotherapy cross-resistance in relapsing tumors may be reversed by activating dendritic cells.

The metabolism of lactic acid has antidepressant effects in mice.

Targeting the epigenetic enzyme DOT1L may reverse some behavioral effects of early-life stress.

LDL-lowering statins can promote the development of an aggressive subtype of pancreatic cancer.

A mutation in the epigenetic machinery creates a metabolic vulnerability in lung cancers.

A pediatric brain cancer often caused by coincident mutations might be treated with a fungal analog.

Subsequent, not concurrent, treatment with CDK4/6 inhibitors improves the efficacy of chemotherapy.

Various studies reveal how we might effectively treat small cell lung cancer.

Studies identify common targets for preventing resistance to KRAS inhibitors.

Stress and advanced age suppress interferon-mediated antitumor immune surveillance and therapy.

Deciphering how macrophages are reprogrammed in disease may lead to better patient therapies.

By pairing up with RNA-binding proteins, p62 promotes melanoma progression.

Neurodegeneration Parkinson's disease is characterized by the progressive loss of dopaminergic neurons that leads to loss of motor control and cognitive decline. Kim et al. found that activating the kinase Akt1, such as with chlorogenic acid (a polyphenol found in coffee), prevented both neuronal death and motor and cognitive impairments in two mouse models of Parkinson's disease. Akt1 inhibited neuronal death by transcriptionally activating a gene involved in regulating programmed cell death. The clinical relevance of this mechanism was supported by correlative data collected from postmortem patient brain tissue. Sci. Signal. 13 , eaax7119 (2020).

Cancer Therapy Although the activity of the epidermal growth factor receptor (EGFR) pathway is increased in triple-negative breast cancers (TNBCs), these tumors are generally insensitive to EGFR inhibitors. Cruz-Gordillo et al. found that insensitivity to the EGFR inhibitor erlotinib was due to the prosurvival protein Mcl-1. MCL1 expression in TNBC cells was promoted by the ELP family of transcription-elongation regulators, particularly ELP4. These findings suggest that combining erlotinib with an Mcl-1 inhibitor might be effective in TNBC patients. Sci. Signal. 13 , eabb9820 (2020).

Alcohol Addiction Alcohol abuse has detrimental cognitive and behavioral consequences. Binge drinking is associated with anxiety in humans and, in mice, activates resident phagocytic immune cells in the brain called microglia. Socodato et al. found that a binge-drinking protocol in male mice induced microglia to selectively scavenge excitatory synapses between neurons in the prefrontal cortex. The loss of these connections did not cause neuronal death during the study but instead depressed neurotransmission and increased anxiety-like behaviors in the mice. Sci. Signal. 13 , eaba5754 (2020).

Cancer Therapy Cell death screens using patient biopsies could be used to identify effective treatments for cancerous solid tumors. However, it takes several days to obtain results, meaning that the cells guiding treatment decisions may become molecularly distinct from those in patients. Bhola et al. developed a high-throughput method that, within 24 hours, identifies drugs that initiate cell death programs in tumor cells from freshly isolated patient biopsies. This method identified drug therapies that shrank breast and colon tumors in mice, but which would not have seemed as promising when screened in cells cultured for several days. Sci. Signal. 13 , eaay1451 (2020).

Pain Until alternatives to opioids are developed, keeping opioid doses low but effective may be key to limiting their adverse effects. Duron et al. found that inhibitors of the chaperone protein Hsp90 enhanced the efficacy of systemically administered opioids in mice. In sensory neuron–rich regions of the spine, Hsp90 attenuated the activity of a kinase-regulated protein synthesis pathway required for the antinociceptive effects of opioids. In mice, blocking Hsp90 in the spine, but not in the brain or periphery, made opioids more effective at dampening sensitivity to heat and touch. Sci. Signal. 13 , eaaz1854 (2020).

For combination therapy, knowing the “how” and “when” is just as important as knowing the “what.”

Drugs that impair DNA repair broaden cancer sensitivity to common therapies.

Several studies identify drug combinations that target or exploit the EWS-FLI1 fusion protein to kill Ewing’s sarcoma cells.

Two studies in this issue of Science Signaling identify how amyloid-β causes various pathological mechanisms in mouse models of Alzheimer’s disease.

Future immunotherapies may stimulate immune system attack as well as memory against cancer to prevent relapse in patients.

This week’s articles describe ways to treat scleroderma and schizophrenia.

This week’s article describes a way to potentially reduce neurodegeneration in patients with Huntington’s disease.

This week’s articles describe a way to treat or prevent pulmonary distress and a way to boost treatments against anemia.

Anti-CSF1R immunotherapy effectively inhibits one suppressive immune cell type but unleashes another through cancer-associated fibroblasts.

This week’s articles describe a better diagnostic marker for pediatric biliary atresia and insights into CAR T cell biology that may enable optimization of CAR T cell–based therapy.

This week’s articles describe why pulmonary hypertension often arises with lung cancer; a way to interrupt the autoimmune response in type 1 diabetes; and a marker through which to screen patients for response to MSC therapy and risk for graft-versus-host disease.

This week’s articles describe a way to combat the negative effects of stress on cancer therapy; a potential target in heart failure; and why nighttime wounds heal more slowly than daytime wounds.

This week’s articles describe new ways to treat some types of GI cancer and various childhood solid tumors.

In this issue of Science Signaling , three papers uncover molecular mechanisms of neurological dysfunction in animal models of fragile X syndrome.

This week’s articles describe new therapeutic targets for pulmonary arterial hypertension, acute myeloid leukemia, and Friedreich’s ataxia.

This week’s articles describe ways to potentially treat obesity-associated disorders and prevent sepsis.

A mutation in p53 enhances its induction of a phosphatase that inhibits YAP, a critical mediator of pancreatic cancer development.

This week’s article and a review describe ways to potentially improve immunotherapy for cancer patients.

This week’s articles describe a stem cell–based therapy for chronic kidney disease and targets for treating diabetic nerve pain and acute respiratory distress in critically ill patients.

This week’s articles describe new therapeutic strategies for cancer, lung inflammation, and graft-versus-host disease.

Inhibiting a mechanism that mediates cognitive deficits caused by antipsychotic drugs may improve clinical outcomes for schizophrenia patients.

This week’s articles show that blocking a prometastatic process unintentionally impairs immunotherapy and report new therapeutic targets in type 2 diabetes and asthmatic lung disease.

This week’s article describes how targeted antimicrobials may reduce the virulence of Clostridium difficile infection.

Chemotherapy triggers gut microbiota to stimulate pain-associated peripheral inflammation.

This week’s articles describe how the immune system in some children is better able to cope with dengue virus infection; how targeting a specific population of monocytes may relieve persistent inflammation associated with HIV infection; and how targeting the vascular niche may suppress fibrosis around lung and liver engraftments.

This week’s articles describe potential therapeutic strategies to reduce hydrocephaly in infants, to kill liver cancer cells, and to improve MeCP2-associated neurological disorders.

This week’s articles describe ways to treat neurodegenerative and neurodevelopmental diseases.

A strategy combining immunotherapies with a tumor-targeted virus may be a new treatment option for glioblastoma patients.

This week’s articles describe a way to prevent a major side effect of chemotherapy, paths of endocrine therapy resistance in breast cancer, and a new treatment for type 1 diabetes.