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Role of ferroptosis on tumor progression and immunotherapy

Ferroptosis is triggered by intracellular iron leading to accumulation of lipid peroxidation consequent promotion of cell death. Cancer cell exhibits ability to evade ferroptosis by activation of antioxidant signaling pathways such as SLC7A11/GPX4 axis. In addition to transcriptional regulation on ferroptosis by NRF2, SREBP1, YAP, and p53, ferroptosis is modulated by ubiquitination or autophagic degradation. Moreover, zinc or Ca2+ could modulate ferroptosis by inducing lipid peroxidation and ferroptosis. Induction of ferroptosis enhances immune cell activity such as T cells or macrophages, which is associated with the release of DAMPs (damage-associated molecular patterns) and IFNγ. Therefore, combined immune checkpoint inhibitors with ferroptosis inducers effectively enhance antitumor immunotherapy, whereas induction of ferroptosis could impair T cell activity or survival, suggesting that rational combined therapy for cancer is essential. In this review, we discussed the regulatory role of ferroptosis on tumor progression and immunotherapy.

D. Gong et al.
Ferroptosis is a type of non-programmed death, which is irondependent cell death, therefore intracellular iron levels are critical for ferroptosis. In this process, TFR1 plays an important role in promoting iron uptake. MYCN induces TFR1 expression in neuroblastoma cancer cells resulting in increased iron levels and lipid ROS production, consequently facilitates ferroptosis in response to inducers such as SAS and auranofin [17]. In addition, YAP increases TFR1 expression resulting in accumulation of intracellular iron levels, and O-GlcNAcylation of YAP enhances this event in HCC [51]. Conversely, intracellular iron levels could be reduced in sterol regulatory element binding protein-2 (SREBP2) expressed circulating melanoma cells from patients. Mechanistically, SREBP2 induces the expression of transferrin resulting in blockade of accumulation of intracellular iron, consequently causes ferroptosis resistance in response to inducers [52]. These findings suggest that TFR1 exhibits an important role in regulating intracellular iron levels and ferroptosis (Fig. 2).

REGULATION OF FERROPTOSIS BY METALLIC IONS
In addition to iron, zinc can induce ferroptosis [80]. Zinc increases breast and renal cancer cell sensitivity to ferroptosis. Mechanistically, zinc transporter-7 (ZIP7) mediates zinc release from  Fig. 2 Regulation of ubiquitination on ferroptosis. Although TFR1 facilitates iron uptake, it will be degraded by β-TRCP ubiquitin ligase leading to ferroptosis resistance. OTUB1 or ABCC5 inhibits SLC7A11 ubiquitination and degradation, and CD44 or H 2 S-mediated persulfidation of OTUB1 enhances this event. However, it is unclear the mechanism of SLC7A11 degradation in proteasome. MIB1 ubiquitin ligase induces NRF2 ubiquitination and degradation, which is reversed by USP11 deubiquitinating enzyme. Under base condition, the interaction of KEAP1 with NRF2 recruits Cul3-RBX1 ubiquitin ligase to NRF2 for proteasomal-dependent degradation in response to ferroptosis inducers (RSL3, cetuximab). However, in response to oxidative stress, KEAP1 dissociates from NRF2 and increases NRF2 protein stability resulting in ferroptosis resistance. Although p14(ARF)/p53 pathway inhibits SLC7A11 resulting in ferroptosis sensitivity, p14(ARF) is degraded by CRL2-KLHDC3 ubiquitin ligase, which in turn causes ferroptosis resistance. D. Gong et al. endoplasmic reticulum to cytosol, which in turn enhances ferroptosis. Cold stress increases lipid peroxidation accumulation and induces ferroptosis in kidney-and liver-derived cell lines, which is associated with (mitochondrial calcium uptake 1-dependent mitochondrial Ca 2+ uptake [81]. However, calcium (Ca 2+ )-mediated ferroptosis could be suppressed by membranespanning 4-domains A15, the endoplasmic reticulum protein, which depletes luminal Ca 2+ stores leading to inhibition of lipid peroxidation accumulation and ferroptosis [82]. Ferroptosis is irondependent cell death, while zinc and Ca 2+ [80][81][82], can induce lipid peroxidation and ferroptosis (Fig. 4), which expand the conception of iron-dependent death, but the mechanism needs to be further identified.

REGULATION OF FERROPTOSIS ON TUMOR IMMUNOTHERAPY AND RADIOTHERAPY
Cancer cell exhibits ability to evade immunotherapy by regulating immune checkpoint signaling pathways, subsequently, escape immune cell surveillance including T cells, macrophages, and dendric cells [18][19][20]. Induction of ferroptosis increases CD8(+) T cell activity [44] and enhances tumor immunotherapy [83]. NC06 treatment triggers ferroptosis in MDSC by inhibiting ASAH2 and enhances CD8(+) T cell activity in tumors [44]. In contrast, TYRO3mediated ferroptosis resistance leads to reduced anti-PD-1/PD-L1 antitumor immunotherapy [83]. MCH-1 undergoes autophagic degradation in pancreatic ductal adenocarcinoma cells leading to escape of immune surveillance [84]. BEBT-908, a dual PI3K/HDAC inhibitor, induces ferroptosis resulting in increased MCH-1 expression and activation of STAT1/IFNγ signaling in cancer cells, which in turn promotes antitumor immunotherapy [85]. In tumor microenvironment, the released IFNγ from CD8(+) T cells suppresses SLC3A2 and SLC7A11 expression on cancer cells, consequently facilitates cancer cell accumulation of lipid peroxidation and ferroptosis [86]. In response to radiotherapy, the released IFNγ from CD8(+) T cells synergistically inhibits SLC7A11 expression leading to activation of ferroptosis, which in turn enhances anti-PD-L1 antitumor immunotherapy [87]. These findings suggest that RSL3, Fin56 ARNTL p62 Fig. 3 Regulation of autophagy on ferroptosis. NCOA4 induces ferritin autophagic degradation leading to the release of iron, which in turn facilitates ferroptosis, while COPZ1 inhibits NCOA4/ferritin pathway. Ferritin could be embedded into multivesicular bodies and traffic out of cells as exosome leading to reduced intracellular iron levels and ferroptosis resistance. In response to inducers, p62-mediated FPN1 or ARNTL autophagic degradation, which in turn promote sensitivity of ferroptosis. Although ferritinophagy is triggered in response to inducers including RSL3, Fin56, DAT etc, the mechanism is unclear.
D. Gong et al.
the additional role of T cell killing to cancer cells by induction of ferroptosis. Since cyst(e)inase treatment can induce intracellular cystine degradation consequent promotion of cancer cell ferroptosis [88], the combined cyst(e)inase with PD-L1 antibody effectively enhances tumor immunotherapy [86], suggesting that combined ferroptosis inducers with immune checkpoint inhibitors could effectively enhance cancer immunotherapy. In contrast to T cell killing to cancer cells by ferroptosis induction, in tumor microenvironment, cholesterol-mediated CD8(+) T cell ferroptosis leads to cancer cell immune escape [89]. In this process, cholesterol induces CD36 expression on tumor-infiltrating CD8(+) T cells, consequently, CD36 triggers uptake of fatty acids in CD8(+) T cells resulting in ferroptosis. In contrast, block of CD36 enhancesant-PD-1 antitumor immunotherapy [89], suggesting that ferroptosis inducers could impair T cell survival. In contrast to CD8(+) T cell killing to cancer cells, T regulatory (Treg) cells exhibit immune tolerance and inhibit antitumor immunotherapy, and high levels of GPX4 in Treg cells prevent lipid peroxidation and ferroptosis. In contrast, blockade of GPX4 enhances antitumor immunotherapy [90]. As a deubiquitinating enzyme, OTUD1 facilitates ferroptosis by IREB2-mediated TRF1 expression in colon cancer cells, which in turn promotes the release of damage-associated molecular patterns (DAMPS) from dying cancer cells, subsequently, DAMPS enhances immune cell activity for killing to cancer cells [91]. As an eat-me signal, SAPE-OOH is distributed on ferroptotic cancer cells, which is recognized by TLR2 on macrophage leading to increased phagocytosis by macrophages [92], suggesting that ferroptosis induction promotes phagocytosis by macrophages. Therefore, ferroptosis modulates tumor immunotherapy by affecting immune cell activity including T cells and macrophages (Fig. 5).

FUTURE PERSPECTIVE
Ferroptosis is triggered by intracellular iron-mediated lipid ROS formation resulting in cell death. Conversely, SLC7A11/GPX4 axis protects cells from ferroptosis by detoxification. In this process, GPX4 exhibits antioxidant role in order to ferroptosis resistance, while it is unclear whether other GPX4 family members including GPX1-3 could inhibit ferroptosis. As an important ferroptosis regulator, ferritin undergoes autophagic degradation by NCOA4. Is In addition to iron, zinc and calcium could induce ferroptosis. ZIP7 mediates zinc release from ER to cytosol resulting in ferroptosis. In addition, cold stress increases lipid peroxidation accumulation and induces ferroptosis, which is associated with MICU1-dependent mitochondrial Ca2+ uptake. However, calcium (Ca2+)-mediated ferroptosis could be blocked by MS4A15, which in turn inhibits ferroptosis.
there any other autophagy receptor for ferritin degradation? or does GPX4 undergo ubiquitination and degradation? Although SLC7A11 undergoes ubiquitination and degradation [57,58], what is the specific ubiquitin ligase for SLC7A11 degradation? Does SLC7A11 undergo autophagic degradation? These issues need to be further determined. The mediators of ferroptotic cells could induce surround-cell ferroptosis [93], while the mechanism is still unclear. Although ferroptosis effectively enhances cancer immunotherapy [44,83,87], induction of ferroptosis could impair T cell survival [89]. Therefore, rational combined immune checkpoint inhibitors with ferroptosis inducers are essential for enhancement of cancer immunotherapy.  Fig. 5 Role of ferroptosis on cancer immunotherapy. Ferroptosis induction facilitates MCH-1 expression, release of DAMPS and IFNγ, which in turn activate immune cell activity including T cells and macrophages. In addition, the release of IFNγ from T cells inhibits Xc (-) system (SLC7A11/SLC3A2), leading to increased ferroptosis sensitivity. Ferroptosis resistance by GPX4 in Treg cells causes immune tolerance. As an eat-me signal, SAPE-OOH is distributed on ferroptotic cancer cells, which is recognized by TLR2 on macrophages leading to increased phagocytosis. Although combined immune checkpoint inhibitors with ferroptosis inducers could effectively enhance antitumor immunotherapy, induction of ferroptosis could impair T cell survival by ferroptosis. Therefore, a rational combined therapy is essential.