iScience. 2026 Mar 11;29(4):115310. doi: 10.1016/j.isci.2026.115310. eCollection 2026 Apr 17.

ABSTRACT

Small cell lung cancer (SCLC) is a highly aggressive tumor with poor prognosis. Ferroptosis is closely linked to tumor antigen presentation: it affects antigen presentation efficiency via immunostimulatory signals, while CD8⁺ T cell activation induced by antigen presentation promotes tumor cell ferroptosis by secreting IFNγ. This study used multi-omics analyses and machine learning to screen key genes, verified by in vitro/in vivo experiments. TRIM36 and CAMK2N2 were significantly upregulated in SCLC, negatively correlating with patient survival, effector memory CD8⁺ T cell infiltration, and tumor MHC I expression. They suppress SCLC antigen presentation via ferroptosis-dependent/independent mechanisms, limiting T cell function. TRIM36 and CAMK2N2 are promising SCLC biomarkers and therapeutic targets, providing clues to unravel ferroptosis-antigen presentation associations in tumor cells and optimize immunotherapeutic strategies.

PMID:41940332 | PMC:PMC13049528 | DOI:10.1016/j.isci.2026.115310

iScience. 2026 Mar 11;29(4):115310. doi: 10.1016/j.isci.2026.115310. eCollection 2026 Apr 17.

ABSTRACT

Small cell lung cancer (SCLC) is a highly aggressive tumor with poor prognosis. Ferroptosis is closely linked to tumor antigen presentation: it affects antigen presentation efficiency via immunostimulatory signals, while CD8⁺ T cell activation induced by antigen presentation promotes tumor cell ferroptosis by secreting IFNγ. This study used multi-omics analyses and machine learning to screen key genes, verified by in vitro/in vivo experiments. TRIM36 and CAMK2N2 were significantly upregulated in SCLC, negatively correlating with patient survival, effector memory CD8⁺ T cell infiltration, and tumor MHC I expression. They suppress SCLC antigen presentation via ferroptosis-dependent/independent mechanisms, limiting T cell function. TRIM36 and CAMK2N2 are promising SCLC biomarkers and therapeutic targets, providing clues to unravel ferroptosis-antigen presentation associations in tumor cells and optimize immunotherapeutic strategies.

PMID:41940332 | PMC:PMC13049528 | DOI:10.1016/j.isci.2026.115310

Phytomedicine. 2026 Mar 27;155:158126. doi: 10.1016/j.phymed.2026.158126. Online ahead of print.

ABSTRACT

BACKGROUND: Mitochondrial damage can induce the release of mitochondrial DNA (mtDNA), leading to oxidative stress and activation of immune responses. Targeting mitochondrial dysfunction may thus represent a therapeutic strategy for gastric cancer. Isobavachalcone (IBC), a prenylated chalcone derived from Psoralea corylifolia L., has demonstrated antitumor activity, but its mechanism of action remains unclear, limiting its clinical application.

PURPOSE: This study aimed to investigate the antitumor effects of IBC in gastric cancer and to elucidate the underlying molecular mechanisms, with a focus on mitochondrial damage and immune activation.

STUDY DESIGN: The study combined in vitro and in vivo assays with multi-omics sequencing and network pharmacology to identify IBC's therapeutic target and downstream signaling pathways.

METHODS: Gastric cancer cells and mouse models were treated with IBC to assess its inhibitory effects. Multi-omics approaches and network pharmacology were used to identify potential targets. ROS production, mitochondrial membrane integrity, and immune pathway activation were evaluated via biochemical and molecular assays.

RESULTS: IBC significantly suppresses gastric cancer growth both in vitro and in vivo. Integrated analysis identifies dihydroorotate dehydrogenase (DHODH) as a direct target of IBC. DHODH deficiency can induce mitochondrial membrane remodeling and STING pathway activation. Inhibition of DHODH by IBC induces ROS accumulation, mitochondrial membrane remodeling, and activation of the STING pathway, promoting antitumor immune responses. This study demonstrates that IBC enhances antitumor immunity in gastric cancer through mitochondrial damage-mediated mechanisms.

CONCLUSION: IBC exerts dual antitumor and immunostimulatory effects in gastric cancer by targeting DHODH, inducing mitochondrial damage, and activating the STING pathway, highlighting its promising therapeutic potential in gastric cancer.

PMID:41931998 | DOI:10.1016/j.phymed.2026.158126

Phytomedicine. 2026 Mar 27;155:158126. doi: 10.1016/j.phymed.2026.158126. Online ahead of print.

ABSTRACT

BACKGROUND: Mitochondrial damage can induce the release of mitochondrial DNA (mtDNA), leading to oxidative stress and activation of immune responses. Targeting mitochondrial dysfunction may thus represent a therapeutic strategy for gastric cancer. Isobavachalcone (IBC), a prenylated chalcone derived from Psoralea corylifolia L., has demonstrated antitumor activity, but its mechanism of action remains unclear, limiting its clinical application.

PURPOSE: This study aimed to investigate the antitumor effects of IBC in gastric cancer and to elucidate the underlying molecular mechanisms, with a focus on mitochondrial damage and immune activation.

STUDY DESIGN: The study combined in vitro and in vivo assays with multi-omics sequencing and network pharmacology to identify IBC's therapeutic target and downstream signaling pathways.

METHODS: Gastric cancer cells and mouse models were treated with IBC to assess its inhibitory effects. Multi-omics approaches and network pharmacology were used to identify potential targets. ROS production, mitochondrial membrane integrity, and immune pathway activation were evaluated via biochemical and molecular assays.

RESULTS: IBC significantly suppresses gastric cancer growth both in vitro and in vivo. Integrated analysis identifies dihydroorotate dehydrogenase (DHODH) as a direct target of IBC. DHODH deficiency can induce mitochondrial membrane remodeling and STING pathway activation. Inhibition of DHODH by IBC induces ROS accumulation, mitochondrial membrane remodeling, and activation of the STING pathway, promoting antitumor immune responses. This study demonstrates that IBC enhances antitumor immunity in gastric cancer through mitochondrial damage-mediated mechanisms.

CONCLUSION: IBC exerts dual antitumor and immunostimulatory effects in gastric cancer by targeting DHODH, inducing mitochondrial damage, and activating the STING pathway, highlighting its promising therapeutic potential in gastric cancer.

PMID:41931998 | DOI:10.1016/j.phymed.2026.158126