Lighting Up the Fire in the Microenvironment of Cold Tumors: A Major Challenge to Improve Cancer Immunotherapy

Benoit, Alice; Vogin, Guillaume; Duhem, Caroline; Berchem, Guy; Janji, Bassam

doi:10.3390/cells12131787

Cited by 15 publications

(15 citation statements)

References 148 publications

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“…The function of these checkpoints is to act as brakes on the immune system, dampening the activity of T-cells and aiding in the promotion of immunosuppression. Moreover, HIF-1α also has the capability of binding to the promoter of the PD-L1 gene, leading to the upregulation of this gene, further deactivating T cells and promoting the escape of the immune system in a manner that may lead to resistance against immune checkpoint inhibitors [32,34].…”

Section: Tumor Immune Escape and Immunotherapy Resistancementioning

confidence: 99%

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Musleh Ud Din,

Streit,

Huynh

et al. 2024

IJMS

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In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

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Section: Tumor Immune Escape and Immunotherapy Resistancementioning

confidence: 99%

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Musleh Ud Din,

Streit,

Huynh

et al. 2024

IJMS

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“…Some immunotherapeutic approaches exhibit notable autoimmune side effects, exemplified by the CTLA‐4‐specific antibody ipilimumab, despite extensive endeavors to disentangle its toxicity from its efficacy and amplify its potential as a regulatory T cell‐depleting antibody [ 182 ]. The constrained clinical advantages observed in a relatively minor proportion of patients can be attributed to various factors, chief among them being the dearth or restricted infiltration of immune cells within the microenvironment [ 183 ].…”

Section: Challenges and Limitationsmentioning

confidence: 99%

Immunologic tumor microenvironment modulators for turning cold tumors hot

Khosravi,

Mostafavi,

Bastan

et al. 2024

Cancer Communications

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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.

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“…The pre-existing immune landscape in the TME predicts malignancy outcomes and response to immunotherapies. As noted above, based on their TME, tumors can be categorized into two general types: ‘hot’ tumors, distinguished by an immunosupportive TME and a positive response to immunotherapy, and ‘cold’ or non-immune reactive tumors exhibiting a poor response to immunotherapy and characterized by an immunosuppressive TME ( Zhang et al, 2022 ; Benoit et al, 2023 ). However, it is crucial to recognize that the distinction between immunologically ‘hot’ and ‘cold’ tumors exists along a spectrum, varying not only among different cancer types but also among individual patients within the same cancer type.…”

Section: Defining the ‘Cold’ Tumor Microenvironmentmentioning

confidence: 99%

“…‘Hot’ tumors show enrichment in CD8 + lymphocytes and M1 TAMs, with low infiltration of MDSCs or CAFs, resulting in a more favorable response to immunotherapy. In contrast, the TME of ‘cold’ tumors is defined by the presence of more Tregs than CD8 + lymphocytes and high infiltration of M2 TAMs, MDSCs, and CAFs ( Benoit et al, 2023 ). Therefore, ‘cold’ and ‘altered’ tumors typically exhibit limited clinical benefits from immune checkpoint inhibitors.…”

Section: Defining the ‘Cold’ Tumor Microenvironmentmentioning

confidence: 99%

Microphysiological systems as models for immunologically ‘cold’ tumors

Gaebler,

Hachey,

Hughes

2024

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically ‘cold’ tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in ‘cold’ tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various ‘cold’ tumors. Understanding the intricacies of the TME in ‘cold’ tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

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Lighting Up the Fire in the Microenvironment of Cold Tumors: A Major Challenge to Improve Cancer Immunotherapy

Cited by 15 publications

References 148 publications

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

Immunologic tumor microenvironment modulators for turning cold tumors hot

Microphysiological systems as models for immunologically ‘cold’ tumors

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