Immune Modulation and Immunotherapy in Solid Tumors: Mechanisms of Resistance and Potential Therapeutic Strategies

Abstract

Understanding the modulation of specific immune cells within the tumor microenvironment (TME) offers new hope in cancer treatments, especially in cancer immunotherapies. In recent years, immune modulation and resistance to immunotherapy have become critical challenges in cancer treatments. However, novel strategies for immune modulation have emerged as promising approaches for oncology due to the vital roles of the immunomodulators in regulating tumor progression and metastasis and modulating immunological responses to standard of care in cancer treatments. With the progress in immuno-oncology, a growing number of novel immunomodulators and mechanisms are being uncovered, offering the potential for enhanced clinical immunotherapy in the near future. Thus, gaining a comprehensive understanding of the broader context is essential. Herein, we particularly summarize the paradoxical role of tumor-related immune cells, focusing on how targeted immune cells and their actions are modulated by immunotherapies to overcome immunotherapeutic resistance in tumor cells. We also highlight the molecular mechanisms employed by tumors to evade the long-term effects of immunotherapeutic agents, rendering them ineffective.

Keywords: emerging strategies; immune cells; immune modulation; immunotherapy; therapeutic outcomes; therapeutic resistance; tumor microenvironment.

Figure 1

Major types of tumor-associated immune cells in the tumor microenvironment (TME). Both tumor-promoting and tumor-suppressing immune cells directly impact the phenotypes and functions in the TME through the release of various cytokines or chemokines. Tumor-promoting immune cells, such as myeloid derived suppressor cell (MDSC), N2-tumor associated neutrophil (N2), regulatory T cell (Treg), M2-tumor associated macrophage (M2), and regulatory B cell (Breg) significantly promote the TME by secreting IL-10, VEGF, TGF-β, MMPs, and IL-35. Conversely, tumor-suppressing immune cells like natural killer cell (NK), N1-tumor associated neutrophil (N1), effector T cell (Teff), M1-tumor associated macrophage (M1), dendritic cell (DC), and effector B cell (Beff) produce perforin or granzymes, IL-12, TNF-α, IL-2, IFN-γ, IL-1, IL-6, and IL-18 that suppress the TME. Created using BioRender.com.

Figure 2

Different contributions to antitumor immune response by cancer immunotherapies. (A) Immune checkpoint inhibitors (ICIs) reverse the immunosuppression mediated by the immune checkpoints, e.g., PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, and VISTA, by selectively inhibiting their receptors. (B) Immunomodulators such as cytokines (IFN-α, IL-1, IL-2, IL-12), adoptive cell transfer (ACT) (mainly CART-T, TCR-T, TIL therapies), and agonist antibodies (OX49, GITR, CD137) stimulate the activation and proliferation of T cells, thereby exerting the antitumor activity. (C) Cancer vaccines based on dendritic cells (DCs), tumor cell lysates (TCLs), nucleic acid, and neoantigens cause an increased uptake of tumor antigens, which results in the activation of antigen presentation cells (APCs) like DCs that directly activate the T cell to kill the tumor cell. (D) Virotherapy by utilizing oncolytic viruses (HSV-1, T-VEC, HadV-C5, C-REV) enhances antitumor response by inducing immunogenic cell death (ICD), resulting in a cascade of events leading to tumor cell clearance. Created using BioRender.com.

Figure 3

Major types of resistance to immunotherapy in patients with cancer. From a clinical perspective, immunotherapy is broadly classified into primary, adaptive, and acquired resistance based on response timing and mechanisms. (A) Primary resistance occurs when a tumor fails to respond to immunotherapy from the outset, often due to adaptive immune resistance. (B) Adaptive immune resistance arises when tumor cells evade destruction by modifying their response to immune attacks, potentially leading to primary resistance, mixed responses, or acquired resistance. (C) Acquired resistance occurs when a tumor initially responds to immunotherapy but later relapses and progresses after a period of control. Grey-colored cells indicate either non-resistant or non-sensitive tumor cells before immunotherapy. Pink- and yellow-colored cells represent different resistant tumor cells and cyan-colored cells indicate sensitive tumor cells. Created using BioRender.com.

Figure 4

Molecular mechanisms of immunotherapeutic resistance in cancer. Tumor cell intrinsic mechanisms involve low uptake and high efflux of drugs, mutation in the targeted genes, loss of tumor-specific antigen expression through lack of T cell responses, downregulation of MHC, alteration of oncogenic signaling via MAPK pathway, and loss of PTEN expression, which promote PI3K signaling and WNT/β-catenin expression signaling pathways, and loss of IFN-γ signaling pathways. Meanwhile, tumor cell extrinsic mechanisms primarily include immunosuppressive cells in the TME, absence of T cells, cellular senescence, and expression of inhibitory immune checkpoints in the tumor cell. Created using BioRender.com.

Figure 5

Intrinsic and extrinsic mechanisms of immunotherapy resistance in tumor cells. The central interactions between different stromal and immune cells of the TME are mediated via the release of corresponding cytokines. Within the TME, tumor-promoting cell populations like CAF, MDSC, N2-TAN, Treg, and M2-TAM either directly promote tumor growth, inhibit the antigen presentation, or directly inhibit the T cell to downregulate the immune response against the tumor cells. Tumor-suppressing cells, particularly NK, M1-TAM, and N1-TAN, enhance T cell response or exert direct tumor-killing activity. The intrinsic mechanisms of resistance in tumor cells include mutation of the targeted gene, modification of oncogenic signaling pathways, deprivation of tumor-specific antigen expression, decreased MHC expression, and low uptake and high efflux of drugs. On the contrary, tumor cell extrinsic mechanisms of resistance mostly include expression of inhibitory checkpoint molecules (PD-L1, Galectin-9 in tumor cells, or PD-1, TIM-3, CTLA-4 in T cells), loss of T cells with specific TCR, and increased activity of immunosuppressive cell populations (MDSC, Treg, M2-TAM, N2-TAN) via the generation of cytokines in the TME. Created using BioRender.com.