Immunologic tumor microenvironment modulators for turning cold tumors hot

Abstract

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune-resistant tumors.

Keywords: cold tumor; hot tumor; immunologic modulator; immunotherapy; therapeutic strategy; tumor microenvironment.

FIGURE 1

Tumor immunophenotypes. Illustration depicting the three‐primary tumor immunophenotypes determined by the presence and distribution of cytotoxic immune cells within the TME. Immune‐inflamed tumors, or hot tumors, characterized by abundant T cell infiltration, heightened IFN‐γ signaling, PD‐L1 expression, and a high TMB, often exhibit increased responsiveness to ICIs. In contrast, immune‐excluded tumors display CD8⁺ T lymphocytes mainly at the tumor invasion margins, while immune‐desert tumors lack CD8⁺ T lymphocytes both within the tumor core and its surrounding periphery. Abbreviations: APC, antigen‐presenting cell; PD‐1, programmed cell death protein 1; PD‐L1, programmed death ligand 1.

FIGURE 2

The complex TME and its impact on tumor behavior. Visual representation of the multifaceted TME composed of various cellular and non‐cellular components. Within the TME, CAFs, pericytes, lymphocytes, adipocytes, neutrophils, Treg cells, mesenchymal stem cells, mast cells, and other immune elements interact and collectively influence tumor progression through mechanisms of immunosuppression. The ECM serves as a critical context for cancer cells, affecting their mobility, invasion, and metastatic potential. Abbreviations: CAF, cancer‐associated fibroblast; ECM, extracellular matrix; IL‐4, interleukin‐4; MDSC, myeloid‐derived suppressor cell; TGF‐β, transforming growth factor‐beta.

FIGURE 3

Hypoxia‐induced immunosuppression in the TME. Visual representation of the impact of hypoxia on the TME. Hypoxia, caused by limited access to nutrients and oxygen, triggers the activation of HIFs, leading to metabolic shifts, increased glycolysis, and the production of lactate and H⁺ ions. Hypoxia in the TME promotes immunosuppression through various mechanisms, including the recruitment of Tregs, the induction of stemness‐associated factor Nanog, and the influence of HIF‐1α on MDSCs and TAMs. Abbreviations: Acetyl‐CoA, acetyl coenzyme A; AMPK, adenosine monophosphate‐activated protein kinase; ARNT, aryl hydrocarbon receptor nuclear translocator; ATP, adenosine triphosphate; BCAAs, branched chain amino acids; HIF‐1α, hypoxia inducible factor‐1 alpha subunit; HIF‐1β, hypoxia inducible factor‐1 beta subunit; HRE, hypoxia responsive element; TCA cycle, tricarboxylic acid cycle; α‐KG, alpha‐ketoglutarate.

FIGURE 4

The characteristics of cold and hot tumors. One of the main features of cold tumors is low immune cell infiltration and the existence of immunosuppressive cells, such as regulatory T cells. In contrast, tumor‐infiltrating lymphocytes are remarkable in hot tumors and anti‐tumor immune response inhibits tumor growth and ultimately, these tumors have better prognoses and outcomes. In this regard, immunotherapies by enhancing the efficacy of tumor‐infiltrating lymphocytes function, provide promising approaches in turning cold tumors into hot ones. Abbreviations: CAR, chimeric antigen receptor; PDL‐1, programmed death‐ligand 1; Treg, T regulatory.

FIGURE 5

Side effects and toxicities of immunotherapy. Illustration depicting the potential side effects and toxicity effects resulting from two cutting‐edge cancer immunotherapies ICIs and CAR‐T Cell Therapies. ICIs may lead to irAEs characterized by immune dysregulation, affecting non‐tumor self‐tissues, while CAR‐T cell therapies can trigger CRS, and in some cases, thrombosis due to their potent immune activation. These therapies represent promising advances in cancer treatment, yet the management of associated side effects is a crucial aspect of patient care. Abbreviations: Ang‐1, angiopoietin‐1 APC, antigen‐presenting cell; CAR‐T cell, chimeric antigen receptor T cell; CTLA‐4, cytotoxic T lymphocyte‐associated protein 4; DAMPs, damage‐associated molecular patterns;gp130, glycoprotein 130; IFN‐R, interferon receptor; IFN‐γ, interferon‐gamma; IL‐2R, interleukin‐2 receptor; IL‐6, interleukin‐6; IL‐6R, interleukin‐6 receptor; IL‐12, interleukin‐12; IL‐1β, interleukin‐1 beta; TLR, toll‐like receptor; TNF‐α, tumor necrosis factor‐alpha; TNFR, tumor necrosis factor receptor; vWf, von Willebrand factor.