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Review
. 2024 Sep 3;10(18):e37376.
doi: 10.1016/j.heliyon.2024.e37376. eCollection 2024 Sep 30.

Targeting autophagy can synergize the efficacy of immune checkpoint inhibitors against therapeutic resistance: New promising strategy to reinvigorate cancer therapy

Mehrdad Hashemi  1   2 , Elaheh Mohandesi Khosroshahi  1 , Mahsa Tanha  3 , Saloomeh Khoushab  1 , Anahita Bizhanpour  1 , Farnaz Azizi  1 , Mahsa Mohammadzadeh  1   2 , Arash Matinahmadi  4 , Zeinab Khazaei Koohpar  5 , Saba Asadi  1 , Hengameh Taheri  1 , Ramin Khorrami  6 , Marzieh Ramezani Farani  7 , Mohsen Rashidi  8   9 , Mahdi Rezaei  10 , Eisa Fattah  11 , Afshin Taheriazam  1   12 , Maliheh Entezari  1   2
Affiliations
Review

Targeting autophagy can synergize the efficacy of immune checkpoint inhibitors against therapeutic resistance: New promising strategy to reinvigorate cancer therapy

Mehrdad Hashemi et al. Heliyon. .

Abstract

Immune checkpoints are a set of inhibitory and stimulatory molecules/mechanisms that affect the activity of immune cells to maintain the existing balance between pro- and anti-inflammatory signaling pathways and avoid the progression of autoimmune disorders. Tumor cells can employ these checkpoints to evade immune system. The discovery and development of immune checkpoint inhibitors (ICIs) was thereby a milestone in the area of immuno-oncology. ICIs stimulate anti-tumor immune responses primarily by disrupting co-inhibitory signaling mechanisms and accelerate immune-mediated killing of tumor cells. Despite the beneficial effects of ICIs, they sometimes encounter some degrees of therapeutic resistance, and thereby do not effectively act against tumors. Among multiple combination therapies have been introduced to date, targeting autophagy, as a cellular degradative process to remove expired organelles and subcellular constituents, has represented with potential capacities to overcome ICI-related therapy resistance. It has experimentally been illuminated that autophagy induction blocks the immune checkpoint molecules when administered in conjugation with ICIs, suggesting that autophagy activation may restrict therapeutic challenges that ICIs have encountered with. However, the autophagy flux can also provoke the immune escape of tumors, which must be considered. Since the conventional FDA-approved ICIs have designed and developed to target programmed cell death receptor/ligand 1 (PD-1/PD-L1) as well as cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) immune checkpoint molecules, we aim to review the effects of autophagy targeting in combination with anti-PD-1/PD-L1- and anti-CTLA-4-based ICIs on cancer therapeutic resistance and tumor immune evasion.

Keywords: Autophagy; Immune checkpoint inhibitors; Neoplasms; Therapy resistance; Tumor escape.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Autophagy flux; from beginning to end. The initiation step of autophagy, i.e. phagophore formation, is provoked by the initiation complex ULK1/2- Atg13-FIP200-ATG101, which can be inhibited by mTOR. In the next step, Vps34 is activated and connects to Beclin1, Vps15, and Atg14 to conduct the nucleation process and further progression of the phagophore formation. The newly generated phagophores are elongated to form autophagosomes under the regulation of LC3-II and Atg12-Atg5-Atg16L complex. In the following, autophagosomes can fuse with either endosomes or lysosomes to degrade and remove subcellular debris, and thus provide an enriched cellular nutrient pool.
Fig. 2
Fig. 2
Dual role of autophagy in cancer. In a tumor cell, autophagy can be activated by tumor suppressor genes/proteins or be inhibited by oncogenes/onco-proteins. In this context, autophagy activation may desirably fight tumor cell, while the inhibited autophagy can result in tumor progression. mTOR and AMPK inhibit the corresponding tumor suppressors, and the same mTOR along with PI3K/Akt stimulate oncogenic factors.
Fig. 3
Fig. 3
Underlying mechanisms by which ICI-related therapeutic response and/or resistance can be developed. Innate or acquired resistance against ICIs is developed due to incomplete formation of anti-tumor T cells, defective expansion of memory T cells, and/or dysfunction of tumor-specific T cells. The absence of appropriate neo-antigens, disordered presentation of tumor antigens, and disrupted immune infiltration inside the tumor are considered the major contributors to incomplete T cell generation (Left). In the case of defective development of memory T cells, T cell epigenetic alterations and T cell exhaustion have been realized to be responsible (Middle). Ultimately, defects in IFN signaling, the presence of immune suppressive cells, and alternate immune checkpoints can result in tumor-specific T cell dysfunction (Right). It should be noted that this figure has illustrated the mechanisms related to ICI therapeutic response.
Fig. 4
Fig. 4
A schematic view of how autophagy correlates with immune evasion of tumor cell.
See this image and copyright information in PMC

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