Why do so few people benefit from cancer immunotherapy?

When the first immunotherapy drug ipilimumab (Yervoy) was FDA approved in 2011, immunotherapy was hailed as a “breakthrough” in cancer treatment. This much-anticipated new therapy harnessed the power of the body’s immune system to fight cancer. Fast forward to today and, unfortunately, only a minority of cancer patients truly benefit from immunotherapy in terms of tumor shrinkage, and even fewer experience long-term survival as a result.

Why did immunotherapy not live up to the hype? It turns out that simply “revving up” the immune system is not enough. Having plenty of cancer-killing natural killer (NK) cells, cytotoxic T-cells (CTCs), M1 macrophages, and dendritic cells (DCs) is insufficient. Tumors have sophisticated strategies to block the function of immune cells and hide tumor cells from the immune system, despite receiving immunotherapy. Some of these mechanisms include:

Tumor hypoxia.
Recruitment of immunosuppressive T-regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs)
Recruitment of tumor-killing M1 macrophages and polarizing them into tumor-promoting M2 macrophages (also known as tumor-associated macrophages or TAMs).
Impaired function of DCs by the intracellular accumulation of cholesterol.
Prostaglandin E2 (PGE2)-triggered immune evasion.
Interaction between platelets and tumor cells.
Iron-induced parafibrin formation blocking immune-mediated destruction.
Tumor collagen density preventing adequate infiltration of immune cells.
Accumulation of activin A.
Lack of sufficient energy by immune cells.
Altered tumor energy metabolism induces an acidic extracellular microenvironment and dampens the expression of major histocompatibility complex-1 (MHC-1), resulting in reduced expression of tumor-associated antigens (TAAs).

To improve the efficacy of immunotherapy, it is important to consider:

Reducing the accumulation of hypoxia-inducible factors using curcumin, resveratrol, and sulforaphane, and improving tumor oxygenation using pentoxifylline.
Reducing tumor-infiltrating Tregs and MDSCs using ivermectin and molecular hydrogen to reduce CTC-damaging peroxynitrite.
Repolarizing tumor-promoting M2 macrophages into tumor-killing M1 macrophages using onionin A, a sulfur-containing compound from onions.
Normalizing of DC lipid content using metformin to phosphorylate and inhibit acetyl-CoA carboxylase (ACC).
Inhibiting cyclooxygenase-2 (COX-2) using celecoxib to restrain the immunosuppression of PGE2.
Reducing platelet aggregation and tumor density using pentoxifylline.
Blocking the formation of parafibrin using curcumin, EGCG, ferulic acid, magnesium, and sodium selenite.
Inhibiting activin A using follistatin.
Supplementing with creatine, a supplement popular with athletes and bodybuilders serves as a “molecular battery” for immune cells by storing and distributing energy to power their fight against cancer.
Targeting cancer energy metabolism using metformin and syrosingopine to inhibit the efflux of immunosuppressive acidic metabolites (e.g., lactate) and increase expression of MHC-1 and TAAs.
Improving the biodiversity of the gut microbiome using a broad-spectrum, soil-based probiotic with prebiotic. Intestinal bacteria not only participate in regulating the body’s immunity but also assist in optimizing the therapeutic effects of immunotherapy.

For more information:

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