Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives

Abstract

Cancer immunotherapy is a type of treatment that harnesses the power of the immune systems of patients to target cancer cells with better precision compared to traditional chemotherapy. Several lines of treatment have been approved by the US Food and Drug Administration (FDA) and have led to remarkable success in the treatment of solid tumors, such as melanoma and small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, and vaccines, while the chimeric antigen receptor (CAR) T-cell treatment has shown better responses in hematological malignancies. Despite these breakthrough achievements, the response to treatment has been variable among patients, and only a small percentage of cancer patients gained from this treatment, depending on the histological type of tumor and other host factors. Cancer cells develop mechanisms to avoid interacting with immune cells in these circumstances, which has an adverse effect on how effectively they react to therapy. These mechanisms arise either due to intrinsic factors within cancer cells or due other cells within the tumor microenvironment (TME). When this scenario is used in a therapeutic setting, the term “resistance to immunotherapy” is applied; “primary resistance” denotes a failure to respond to treatment from the start, and “secondary resistance” denotes a relapse following the initial response to immunotherapy. Here, we provide a thorough summary of the internal and external mechanisms underlying tumor resistance to immunotherapy. Furthermore, a variety of immunotherapies are briefly discussed, along with recent developments that have been employed to prevent relapses following treatment, with a focus on upcoming initiatives to improve the efficacy of immunotherapy for cancer patients.

Mangifera indica L . kernel ethanol extract inhibits cell viability and proliferation with induction of cell cycle arrest and apoptosis in lung cancer cells

“…Cancer therapeutics are developed to regulate uncontrolled cell proliferation and abnormal mass formation that interferes with the body’s vital functions during the development of tumors. 7 , 49 , 50 However, the most common cancer therapeutic strategy, the use of chemicals that induce apoptosis of cancer cells, has low specificity toward cancer cells and can be toxic to normal host cells. 17 , 51 …”

“… 9 , 10 As a result, there is a pressing need for alternative therapeutic options, such as targeted treatments, immune-based therapies, and the use of natural compounds with fewer side effects and improved effectiveness. 11 , 12 Researchers have recently turned their attention to plant-derived compounds, exploring their potential anticancer properties to discover new agents with greater specificity, reduced toxicity, and a lower risk of resistance development. 13–15 The investigation of bioactive compounds in plants, including flavonoids, tannins, and phenols, has uncovered promising leads for the development of innovative anticancer drugs.…”

Overcoming Resistance Mechanisms to Immune Checkpoint Inhibitors: Leveraging the Anti-Tumor Immune Response

“…For example, in the hypoxic TME, MDSCs express hypoxia inducible factor 1α (HIF1α) which upregulates cell surface expression of PD-L1 in both MDSCs and tumor cells. Hypoxia-induced HIF1α expression in tumor-infiltrating lymphocytes (TILs) increases PD-1 expression as well [47]. With increased expression and binding of PD-1 with PD-L1, tumor cells are able to activate the immune checkpoint, promote T cell exhaustion and thereby ICI resistance.…”

“…With increased expression and binding of PD-1 with PD-L1, tumor cells are able to activate the immune checkpoint, promote T cell exhaustion and thereby ICI resistance. As well, high lactate and low glucose levels in the hypoxic TME also leads to gene expression changes in CD4+ and CD8+ effector T cells, including inactivation of nuclear factor of activated T cells (NFATs), which in turn leads to suppression of the production of pro-inflammatory IFN-γ needed to potentiate the anti-tumor immune response [47,48].…”

The tumor-intrinsic role of the m 6 A reader YTHDF2 in regulating immune evasion

“…Immunotherapies exhibit the hallmarks of breaking immunosuppressive barriers or boosting existing antitumor immunity ( 1 , 2 ). Despite successes observed with current strategies, patient resistance to immunotherapy is frequently observed because of tumor immune evasion ( 3 , 4 ). Tumors have the intrinsic capability to promote a suppressive microenvironment and evade immune surveillance ( 5 ), which ultimately results in immune evasion and thus limits the efficacy of current immunotherapy.…”