Fig. 2: Co-stimulatory, co-inhibitory and checkpoint pathways.

In addition to the co-stimulatory, co-inhibitory and checkpoint pathways, there are other stimulatory and inhibitory pathways (respectively indicated by upward and downward arrows,) that impact the immune response, including tumor necrosis factor (TNF)-related molecules, other members of the CD28 family, adhesion molecules, and T-cell immunoglobulin and Mucin (TIM) molecules. Various stimulatory and inhibitory pathways can affect the onset of ferroptosis in immune cells and tumor cells via a wide range of mechanisms, ultimately facilitating (green plus) or inhibit (red minus) immune tolerance. Moreover, prostate cancer cells could upregulate PD-L1 through HnRNPL over-expression, which in turn inhibits IFN-γ released by CD8 + T cells via the STAT1/SLC7A11/GPX4 signaling axis. Subsequently, the expression of SLC3A2 and SLC7A11 (two subunits of system Xc-) increases, suppressing lipid peroxidation by facilitating cystine uptake, which ultimately contributes to ferroptosis evasion and dampens tumor immunity. Likewise in GBM, activated CD8 + T cells could release IFN-γ, inducing ferroptosis in cancer cells. Fe3O4-siPD-L1@M-BV2, a novel GBM-targeted pharmaceutical delivery system, could stimulate ferroptosis for immunotherapy of drug-resistant GBM and establish a cascade of amplification between ferroptosis and immune activation.