Table 3.
Combination therapeutic strategies targeting ferroptosis.
| Combination type | Combination regimen | Mechanistic synergy | Applicable drug-resistant cancer types | Efficacy (preclinical/clinical) | Advantages | Disadvantages | References |
|---|---|---|---|---|---|---|---|
| Ferroptosis Inducer + Radiotherapy | Erastin + Ionizing Radiation (IR) | IR upregulates SOCS2 → SLC7A11 degradation → GSH depletion; Erastin blocks System Xc- → synergistic lipid peroxidation | HCC (radiation-resistant), NSCLC (cisplatin-radiation resistant) | HCC: Radiosensitivity ↑35%; SOCS2+ tumors: Pathological complete response (pCR) ↑28% | Enhances radiation-induced oxidative stress; targets radioresistant subclones | Erastin’s poor water solubility requires frequent dosing | (200, 201) |
| RSL3 + Stereotactic Body Radiation Therapy (SBRT) | SBRT increases mitochondrial ROS → lipid peroxide initiation; RSL3 inhibits GPX4 → peroxide accumulation | Pancreatic cancer (gemcitabine-radiation resistant), melanoma (BRAF inhibitor-radiation resistant) | Pancreatic cancer xenografts: Tumor growth ↓60%; Melanoma: Tumor regression ↑55% | SBRT’s focal delivery reduces normal tissue damage; RSL3 bypasses GPX4-dependent resistance | RSL3 induces dose-dependent renal toxicity | (202, 203) | |
| Ferroptosis Inducer + Immunotherapy | Erastin + PD-1 Inhibitor (Pembrolizumab) | PD-1 inhibitor restores CD8+ T cells → IFNγ secretion → SLC7A11 downregulation; Erastin blocks cystine uptake | TNBC (platinum-resistant), NSCLC (immune checkpoint inhibitor-resistant) | TNBC (Phase II): pCR rate 32% (vs. 18% PD-1 monotherapy); NSCLC: Disease control rate (DCR) ↑40% | Establishes “immune-ferroptosis” positive feedback; improves T cell infiltration | Immune-related adverse events (irAEs: rash, colitis) in 15–20% patients | (204, 205) |
| RSL3 + PD-L1 Inhibitor (Atezolizumab) + CD47 Antibody | PD-L1 inhibitor enhances IFNγ → ACSL4 upregulation; RSL3 inhibits GPX4; CD47 antibody depletes M2-TAMs (suppress ferroptosis) | Melanoma (BRAF inhibitor-resistant), RCC (TKI-immune resistant) | Melanoma: CD8+ T cell infiltration ↑2.5-fold; RCC: Objective response rate (ORR) ↑38% | Dual targeting of ferroptosis and immunosuppressive TAMs; overcomes TME-mediated resistance | Higher irAE risk (25–30% patients); CD47 antibody causes transient anemia | (206, 207) | |
| Ferroptosis Inducer + Chemotherapy | Dihydroartemisinin (DAT) + Cisplatin | DAT expands labile iron pool (LIP) → Fenton reaction; Cisplatin induces DNA damage → oxidative stress amplification | Ovarian cancer (carboplatin-resistant), head and neck cancer (cisplatin-resistant) | Ovarian cancer: Cisplatin IC50 ↓50% (resistant cells); Head and neck cancer: Tumor volume ↓65% | DAT’s low toxicity; synergizes with chemotherapy’s oxidative effects | Cisplatin-induced nephrotoxicity persists; DAT requires iron level monitoring | (208, 209) |
| Sulfasalazine + Doxorubicin + Nab-Paclitaxel | Sulfasalazine blocks System Xc-; Doxorubicin generates ROS; Nab-Paclitaxel disrupts membranes → enhanced lipid peroxidation | Breast cancer (doxorubicin-resistant), gastric cancer (taxane-resistant) | Breast cancer (adjuvant setting): Tumor recurrence ↓40%; Gastric cancer: ORR ↑32% | Nab-Paclitaxel improves drug delivery; multi-mechanism attack on resistant cells | Doxorubicin-induced cardiotoxicity; sulfasalazine causes GI upset | (210, 211) | |
| Ferroptosis Inducer + Targeted Therapy | Sorafenib + Lapatinib (EGFR/HER2 Inhibitor) | Sorafenib upregulates ACSL4; Lapatinib inhibits HER2 → reduced Nrf2 activation (blocks GPX4 upregulation) | HER2+ breast cancer (lapatinib-resistant), HCC (sorafenib-resistant) | HER2+ breast cancer: Tumor growth ↓58%; HCC: Progression-free survival (PFS) ↑2.3 months | Targets oncogenic signaling + ferroptosis; overcomes Nrf2-mediated resistance | Lapatinib-induced rash; sorafenib causes hand-foot skin reaction | (212, 213) |
| Ferroptosis Inducer + Epigenetic Modulator | RSL3 + Vorinostat (HDAC Inhibitor) | Vorinostat upregulates ACSL4 (via promoter demethylation); RSL3 inhibits GPX4 → lipid peroxide accumulation | Ovarian cancer (platinum-resistant), CRC (5-FU-resistant) | Ovarian cancer: Ferroptosis sensitivity ↑60%; CRC: Tumor growth ↓52% (xenografts) | Epigenetic preprocessing reverses “ferroptosis desensitization”; low off-target toxicity | Vorinostat causes thrombocytopenia; RSL3-GPX4 inhibition risks normal tissue damage | (214, 215) |