3.3, Crosstalk between ferrode death and rt-induced other cellular effects

From a signal transduction perspective, there seems to be a crosstalk between the DNA damage response and ferrodynamics. IR induces DNA damage, thereby activating ATM, P53 or RB, which may be associated with RT-induced ferrodynamics and other types of RCD, including apoptosis, necrosis and autophagy, collectively known as immunogenic cell death (ICD).

RT-induced autophagy may promote ferrodystrophy through ferritin, lipid, phage clock and/or chaperone-mediated autophagy. Therefore, the immune system and autophagy may be involved in the cross-process of RT-induced DNA damage and iron cell apoptosis.

3.3, Crosstalk between ferrode death and rt-induced other cellular effects

At the molecular level, ATM or P53-mediated crosstalk between iron cell apoptosis and other types of RCD may be mediated by multiple regulators.

In addition to regulating p21-mediated senescence, ampK is at least partially involved in IR-induced autophagy by eliminating mammalian target rapamycin (Mtor)-mediated autophagy or promoting beclin1-mediated autophagy.

IV. Potential therapeutic role of ferrodystrophy in RT-mediated tumor suppression

The focus points to discuss the correlation between ferrodynamic treatment in rt include: (1) whether ferrodynamic and its regulatory factors regulate radiosensitivity, (2) whether targeted ferrodynamics helps radiosensitization, and (3) how to further combine immunotherapy to target ferrodynamics in rt therapy.

4.1, Ferrodysmortality-mediated radiosensitivity

Some studies have found that ir induces expression of SLC7a11 and GPX4 as an adaptive response to protect cells from ferrous death and helps with radiation resistance

4.1, Ferrodysmortality-mediated radiosensitivity

b: The deletion or inhibition of slc7a11 (or gpx4) can achieve significant radiation sensitivity by promoting rt-induced ferrodystrophy;

c: Inactivation of acsl4 inhibits the biosynthesis of pufa-pls, thereby inhibiting rt-induced ferrodystrophy and causing radiation resistance;

Ablation of d:acsl3 reduces the biosynthesis of mufa-pls, resulting in enhanced IR-induced ferrodynamics and radiation sensitivity of cancer cells.

A:Ros is involved in POR-mediated lipid peroxidation and ferrous death, and hypoxia-induced ros and hif activation appears to promote ferrous death.

Iron death plays an important role in RT-mediated tumor suppression, so inducing ferrodynamics in RT-resistant tumors is a promising radiosensitization strategy.

4.2. Radiotherapy combined with fins makes tumors sensitized to radiation

Ferrodysmortality inhibitor treatment confirmed that sas-mediated radiosensitization is indeed mediated by ferrodysemia;

I-type fins combined with RT showed good tolerance in vivo. Overall, promoting RT-induced ferrodystrophy using compounds targeting SLC7a11 may be a promising in vivo radiosensitization strategy.

Inhibition of gsh synthesis or targeting gpx4 may provide an alternative to radiosensitization.

Recent studies have also shown that rsl3, ml162 and fin56 have strong radiosensitization effects in vitro, however, these drugs are not suitable for in vivo treatment due to their poor pharmacokinetics.

4.2. Correlation between ferrodemortem and rt combined immunotherapy

Activated CD8T cells secrete ifnγ during immunotherapy. Ifnγ will downregulate the expression of slc7a11 (and its regulatory partner slc3a2), thereby inhibiting cancer cells' uptake of cystine, thereby enhancing lipid peroxidation and ferrous death. Immune checkpoint inhibitor (ICIS) combined with enzyme enhances tumor ferrodynamics and T-cell-mediated anti-tumor immune response.

The effect of liver metastasis on the effectiveness of immune checkpoint inhibitors in patients with solid malignant tumors has become the focus of several recent clinical and translational studies. We reviewed the literature describing liver immune function, especially the mechanistic observations in these studies. Initial clinical observations showed that pembrolizumab was much worse in patients with melanoma and non-small cell lung cancer (NSCLC) liver metastasis. Subsequently, other clinical studies expanded and reported programmed death in many cancers-1(p

Similar findings of D-1) and programmed death ligand-1 (PD-11) inhibitors. Two recent transformation studies in animal models have dissected the mechanism of this systemic immunosuppression. In both studies, cd11b inhibitory macrophages produced by liver metastasis in the two-site mc38 model appear to delete cd8t cells in a Fasl-dependent manner. In addition, activation of regulatory T cells (Tregs) was observed and involved in distal immunosuppression.

The metastatic sites of solid tumors have different effects on treatment outcomes; such as liver metastasis, which has a disproportionate effect on survival and treatment response in the context of immunotherapy. We review recent advances in experiments and translation, showing that a systematic anti-cancer immune response can be shaped by the liver. The liver is unique in anatomical, histological and functional. It processes blood from the intestine through complex lobular structures, detoxifies and extracts nutrients from portal vein blood. It is immunologically unique in terms of the number and type of cells processed by conventional and unconventional antigens that enable the liver to be the same

T cells that tolerate harmless nutrition and symbiotic bacterial antigen loads from the intestine, and usually can produce an effective immune response to pathogens. Anatomically, the liver has portal vein inflow and central vein outflow, arranged in a hexagonal lobular structure, with pores in the capillaries, and circulating T cells and liver cells can be directly in contact. There are also unique organs between the liver, and the liver can regenerate up to 90% of the volume. This compensatory hyperplasia is not due to a special population of stem cells in the intestine, skin or bone marrow, but is present in the central area of ​​the liver and can be activated after infection, injury or hepatectomy.

In humans, liver transplant recipients require less immunosuppression than kidney or heart transplant recipients. In addition, patients with liver transplants can deviate from immunosuppression (which is not possible in kidney or heart transplants in most cases), and liver grafts can tolerate other types of grafts, such as kidney, heart or skin grafts. Interestingly, injection of antigens into the portal vein (compared to the inferior vena cava) leads to tolerance. These data emphasize that the liver can regulate systemic immune responses. Liver transplant tolerance remains

Among several proposed mechanisms. One model is that antigen presenting cells (APCs), kupfer cells, stellate cells and hepatic sinusoidal endothelial cells (lsec) in the liver present antigens in a tolerant manner. Therefore, allogeneic specificity cultured in the liver t                                                                                                                                                                                                                        �

It is speculated that some viruses [e.g., hepatitis C virus, hepatitis B virus (hbv)] “hijacked” the liver’s tolerance mechanism, resulting in the ineffective or brief initiation of ctl and subsequent incomplete clearance of infection. Interestingly, virus-specific cd4 and cd8 t                                                                                                                                                                                                                    �

Related. There are multiple inhibitory pathways that lead to t                                                                                                                                                                                                                                                       �

Article ideas

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T-cell initiation in lymphoid tissue and tumor microenvironment

Recent studies have highlighted the importance of antigen cross-presentation and co-stimulation of dendritic cells (DC) to naive T cells for effective immunotherapy. In lymphoid tissue or tumor microenvironment (TME), type 1 conventional dc                                                                                                

The frequency in tme                                                                                                                            �

T-cells in the liver start up

In contrast to the above effective priming, in the liver, priming usually results in tolerant or unresponsive T cells. The portal vein blood is filled with microbial products from the intestine, including endotoxin lipopolysaccharides (lps). The persistent low levels in portal vein blood entering the liver can lead to toll-like receptors of various hepatocyte types 4       (tlr4). The liver contains a large number of diverse APCs, including a large number of plasma cell and myeloid

dc, resident hepatic macrophages, lsec      and hepatic stellate cells (hsc). All of these cells are able to present antigens to t                                                                                                                                                                                                                                    

Unlike Kupffer cells, lsec is fully capable of cross-presenting antigens to t cells, but expressing pd-l1 can promote t cells aversion. Hepatocytes can also interact directly with t cells, but their cross-presentation of antigens in the absence of costimulation will lead to t cells incompetence. In this regard, there is an interesting data on Kupffer cell presentation.

HBV core or envelope antigen leads to effective initiation and teff differentiation, while hepatocytes present the core or envelope leads to dysfunctional cd8 cells, which can be rescued by il2, but cannot be blocked by pd-1. These data suggest that liver tolerance is achieved by the immunosuppressive networks of different cell types and the complexity of liver priming.

Clinical data on the treatment of liver metastasis by Ici

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Tumeh                                                                                                                                                                                                                                                              

In the publication, the pfs (median pfs, 5.1 months) in the liver metastasis subgroup were shown to be reduced compared with patients without liver metastasis (median pfs, 20.1    months; p< 0.0001); this finding was confirmed in a separate validation cohort. These findings were replicated in patients with non-small cell lung cancer (NSCLC); here, pfs                                                                                                                                                                                                  �

Given the differences in clinical responses, Tumeh and colleagues studied whether the infiltration margin of cd8t cells in biopsy samples of patients with liver metastasis of melanoma was reduced, which was reported to be associated with the response of pd-1. In fact, among the 61 patients, fewer cd8t cells were found in non-responders compared to those who responded to pd-1 (as previously reported).

In addition, compared with the non-hepatic metastasis group, the cd8t cell count at the edge of infiltration in the liver metastasis group was also significantly reduced (the mean count of the liver metastasis group is 547, the mean count of the non-hepatic metastasis group is 1,441; p<0.016). In addition, in 35 non-hepatic (mainly skin) biopsies from patients with liver metastasis, a decrease in cell infiltration was observed at these distant non-hepatic metastasis edges.

The presence of liver metastasis is also associated with poor prognosis in other tumor types. In nsclc, Sridhar and colleagues examined 569 patients and 1,108 trials of atlantic, who received 10 mg/kg pd-l1 each 2 weeks

Inhibitors   durvalumab     treatment. A multivariate cox     proportional hazard analysis found that the presence of liver metastasis was correlated with poorer ORR, PFS and OS                                                                                                                                                                                                                         

     2.20(p<0.0001), and in 1,108 experimental studies, OS                                                                                                                                                                                                                                          �

In meta-analysis, the results showed that the hr of liver metastasis was 1.73 (hr    ?    1.73; 95%    ci, 1.35–2.20; i2?   69.4%; p    <     0.001). Overall, these data highlight the reduction in clinical benefits obtained by patients with liver metastasis from ici                                                                                                                                                                                         �

Translation model of liver metastasis

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So far, the generation and use of isogenic cell lines that match many different mouse genetic backgrounds have enabled the study of Ici, with response rates similar to what is seen in the clinical setting. Although single-tumor isogenic immunity mouse models are already useful, alternative models are needed to reproduce the complexity of human cancer. For example, immunotherapy is mainly used in metastatic or unresectable diseases, accounting for about 90% of cancer-related deaths, which increases the possibility that most unit-point mouse models currently do not capture the complexity of metastatic cancer immunobiology. Observation of decreased efficacy of systemic immunotherapy in patients with liver metastasis suggests that tumor involvement in specific organs can affect systemic anti-tumor immunity or affect distant tumor sites.
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