Skip to main content
. 2026 Jan 13;16:1726210. doi: 10.3389/fimmu.2025.1726210

Figure 2.

Illustration showing interactions between CD8+ T cells and drug-resistant cancer cells. It details pathways for PD-1/PD-L1 binding, inhibition of CD8+ T cell activity, and mechanisms of ferroptosis resistance, including cystine uptake and GPX4 activation. It highlights a joint strategy using ferroptosis inducers and chemotherapy to counter resistance, with components like erastin, cisplatin, and DAT. The graphic emphasizes the roles of ACSL4, TfR1, and GSTP1 in cancer cell survival and immune response.

Synergistic mechanisms of PD-1/PD-L1 inhibitors combined with ferroptosis inducers (and chemotherapy) against drug-resistant cancer. Left: PD-L1 overexpression on drug-resistant cancer cells binds to PD-1 on CD8+ T effector cells, transmitting inhibitory signals to suppress T cell activity. PD-1/PD-L1 inhibitors block this interaction, restoring CD8+ T cell function—activated CD8+ T cells secrete IFNγ, which upregulates ACSL4 (by 2.8-fold) to promote PUFA-CoA synthesis. LPCAT3 esterifies PUFA-CoA into PUFA-PLs (lipid peroxidation substrates), enhancing ferroptosis sensitivity. Middle: Ferroptosis inducers target key antioxidant pathways—Erastin inhibits System Xc- (blocking cystine uptake, reducing GSH synthesis), while RSL3 directly inhibits GPX4 (impairing PLOOH clearance). Drug-resistant cancer cells with high SLC7A11 expression exhibit ferroptosis resistance, which is reversed by the combined action of immunotherapy and ferroptosis inducers. Right: Immunosuppressive factors in the tumor microenvironment—M2-type tumor-associated macrophages (TAMs) secrete IL-10 to upregulate GSTP1 (enhancing antioxidant defense, suppressing ferroptosis). Bottom: Joint chemotherapy strategy (DAT + Cisplatin): DAT expands the labile iron pool (LIP) via TfR1 to promote Fenton reaction-mediated •OH generation; Cisplatin induces DNA damage and ROS accumulation, synergizing with ferroptosis to kill drug-resistant cancer cells.