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Review
. 2023 Dec 15;15(24):5857.
doi: 10.3390/cancers15245857.

Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance

Liqin Yao  1 , Qingqing Wang  2 , Wenxue Ma  3
Affiliations
Review

Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance

Liqin Yao et al. Cancers (Basel). .

Abstract

Cancer immunotherapy has ushered in a transformative era in oncology, offering unprecedented promise and opportunities. Despite its remarkable breakthroughs, the field continues to grapple with the persistent challenge of treatment resistance. This resistance not only undermines the widespread efficacy of these pioneering treatments, but also underscores the pressing need for further research. Our exploration into the intricate realm of cancer immunotherapy resistance reveals various mechanisms at play, from primary and secondary resistance to the significant impact of genetic and epigenetic factors, as well as the crucial role of the tumor microenvironment (TME). Furthermore, we stress the importance of devising innovative strategies to counteract this resistance, such as employing combination therapies, tailoring immune checkpoints, and implementing real-time monitoring. By championing these state-of-the-art methods, we anticipate a paradigm that blends personalized healthcare with improved treatment options and is firmly committed to patient welfare. Through a comprehensive and multifaceted approach, we strive to tackle the challenges of resistance, aspiring to elevate cancer immunotherapy as a beacon of hope for patients around the world.

Keywords: adoptive cell therapies; cancer immunotherapy; cancer vaccines; combination therapies; immune checkpoint targets; personalized medicine; resistance; tumor microenvironment.

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Conflict of interest statement

The authors confirm that the research was undertaken without any commercial or financial affiliations that might be perceived as potential conflicts of interest.

Figures

Figure 1
Figure 1
The keys to overcoming immunotherapy resistance. Schematic representation of cellular interactions within the hypoxic TME. Cancer cells are surrounded by various cells, including Treg, CTLs, NK cells, TAM, TAN, MDSCs, etc. CTLs and NK cells exhibit PD-1 receptors that interact with PD-L1 expressed by TAM2, MDSCs, and DCs in the hypoxic TME. TAMs can undergo polarization and differentiation influenced via the hypoxic TME. TAM1 exhibits antitumor, while TAM2 promotes tumors. MDSCs release a series of cytokines (b-FGF, IGF-1, IL-10, IL-4, IL-1β, SDF-1, and MCP-1) affecting cancer cell behavior. TGF-β and IL-10 act as regulatory molecules inhibiting CTLs and NK cells, respectively. While the MHC I molecule and tumor antigen facilitate the interaction between cancer cells and CTLs, TAN1, and TAN2, differentiated from TAN, play the roles of inhibiting and promoting cancer cells, respectively. This figure illustrates the complex network of cellular interactions within the hypoxic TME.
Figure 2
Figure 2
Targets of immunotherapeutic agents in cancer therapy. (A) Illustration of the TME featuring cancer cells surrounded by various immune cells and extracellular matrix components. (B) Depiction of immune checkpoint inhibitors (ICIs) such as CTLA-4 and PD-1 (e.g., ipilimumab, pembrolizumab, nivolumab, cemiplimab) binding to their respective receptors on T cells, preventing immune evasion by cancer cells. (C) Representation of CAR T-cells targeting tumor-associated antigens (TAAs) on cancer cells, triggering cytotoxic responses. (D) Macrophage checkpoint inhibition: anti-CD47 mAb blocks the “don’t eat me” signal on cancer cells, promoting their phagocytosis by macrophages. (E) Depiction of dendritic cells (DCs) presenting tumor antigens to naïve T cells, leading to their activation and the initiation of an adaptive immune response against cancer cells. (F) Illustration of activated NK cells targeting cancer cells, mediated by cytokine signaling (e.g., IFNγ production), which enhances the innate immune response against tumors.
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Grants and funding

This research received no external funding.