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Turning cold tumors hot: from molecular mechanisms to clinical applications
Abstract
Immune checkpoint blockade (ICB) therapies have achieved clinical benefit, but most 'immune-cold' solid tumors are not responsive. The diversity of immune evasion mechanisms remains a key obstacle in turning nonresponsive 'cold' tumors into responsive 'hot' ones. Therefore, exploring the mechanisms of such transitions and tumor immunotyping can provide significant insights into designing effective therapeutic strategies against cancer. Here, we focus on the latest advances regarding local and systemic regulatory mechanisms of immune responses in cold and hot tumors. We also highlight the necessity for tumor immunotyping through the assessment of multiple immunological variables using various diagnostic techniques and biomarkers. Finally, we discuss the challenges and potential clinical applications of immunophenotyping to turn cold tumors hot, which may further guide combined immunotherapies.
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“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).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Zhang et al., 2022
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“9 A comprehensive understanding of these microenvironments and identifying the molecules involved in the formation of these immune-activated microenvironments is needed because tumor immune microenvironment regulators are promising immunotherapeutic targets for cancer.”
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“…inhibitors have radically changed treatment for manytypesofcancer, buttheirclinicalapplicationhasbeenlimited by a low response rate, especially in tumors that are characterized by scarce in fi ltration of functional cytotoxic T lymphocytes into the tumor bed and an unin fl amed phenotype (52).”
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“However, tumors with low T cell in fi ltration, so called “ cold tumors ” , are resistant to the ICB treatment [4].”
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“This breakthrough has prolonged the survival of patients with relapsed or refractory metastatic cancers; however, only a subset of patients display favorable responses and most patients with immunologically cold solid tumors do not respond [46,47].”
BackgroundKLF12 overcomes anti-PD-1 resistance by reducing galectin-1 in cancer cells
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“202 In summary, the multiple potential mechanisms governing the circulation and trafficking of antitumour Teffs suggest a promising niche for combination immunotherapy regimens.”
BackgroundSelf-citationTargeting glutamine metabolism crosstalk with tumor immune response
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“37,38 43 Despite the appealing concept, the clinical performance of bispeci fi c antibody monotherapies has fallen short of expectations, as seen in phase III trials of bintrafusp alfa (with an ORR of 10% in BTC), 40,44 highlighting the need for optimization of drug design and exploration of…”
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“Tumors are categorized into hot (immune-inflamed) tumors and cold (immune-desert) tumors based on the infiltration level of T lymphocytes and other immune cells in the tumor microenvironment (TME) 3 .”
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“More inflammatory cytokine infiltration in tumors could facilitate the transformation of “cold” tumors into “hot” tumors and participate in the anti ‐ tumor process[37–39].”
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“50,51 Meanwhile, various non-malignant conditions such as inflammation and wound healing cause upregulation of the same target molecules employed in tumor targeting.”
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“…in fl uenced by various tumor cell-intrinsic and -extrinsic factors including tumor cell immunogenicity, tumor-in fi ltrating T cell repertoire, T cell proliferation, and T cell functional exhaustion, all of which impact the establishment of the TME and in fl uence its antitumor immune response (17).”
On the Biology and Therapeutic Modulation of Macrophages and Dendritic Cells in Cancer
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“Therefore, the key to improving the response rate to immunotherapy is to turn cold tumors into hot tumors with a high degree of immune cell infiltration [4, 5].”
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“253 261 Despite this, the response to CTLA-4-targeting antibodies (e.g., ipilimumab) correlates with high intratumoral CD8 + T cell density, 262 and exceptional responders to pembrolizumab (anti-PD-1) tend to have higher MSI, TMB, and dMMR. 263 Notably, these genetic alterations occur in about 3%–…”
TIM3-blockade synergizes with IL2 in alleviating intra-tumoral CD8+T cell exhaustion
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“Theef fi cacyofTcelltherapyinsolidtumorsisoftenhamperedbytheir ability to navigate, penetrate, activate, or expand inside the immuno-suppressive TME 31,36 .”
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“The TIME can be divided into two categories: infiltrated–excluded also known as “Cold tumors”, where CD8 + T cells are prevented from entering the tumor core, and infiltrated–inflamed also known as “Hot tumors”, which are characterized by highly activated CD8 + T cells that express IFN-γ [20–22].”
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““Cold” tumors are characterized by a lack of T cell infiltration, whereas “hot” tumors are characterized by high levels of T cell infiltration and activity (26).”
BackgroundLan, X., Liang, J.-G., Wen, C., Quan, X.-L., Lin, H.-W., Xu, Q.-Q., Chen, P.-X., Yao, G., Zhou, D., & Yu, M. (2023) · Chinese Chemical Letters · doi:10.1016/j.cclet.2023.108616 · Cited by 15
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“Among these, immune-inflamed tumors exhibit the most favorable response to immunotherapy [4, 5].”
Shi, M., Jia, J.-S., Gao, G., & Hua, X. (2024) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2024.101695 · Cited by 14
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“Our study revealed a previously unrecognized mechanism of immune diversion, expanding the concept of effector immune cell deployment 42 .”
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“However, increasing findings suggest that the infiltration level of T cells might be necessary but insufficient to define “hot” and “cold” tumors, which raised questions on how to identify ICI responders precisely (51).”
Considerations on the Design of Lipid-based mRNA Vaccines Against Cancer
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Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions
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“These distinct immunophenotypes define the immune response to ICIs, out of which the immune-desert or immune-excluded tumor phenotypes are referred to collectively as cold tumors that represent low response rates to ICIs [61].”
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“Whereas hot tumors resemble an immuneinflamed phenotype characterized by infiltration of T lymphocytes, cold tumors present an immune-desert or immune-excluded phenotype with the absence or exclusion of Tcells [61].”
BackgroundMicrophysiological systems as models for immunologically ‘cold’ tumors
Gaebler, D., Hachey, S. J., & Hughes, C. C. W. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1389012 · Cited by 14
“…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).”
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“The current strategy to overcome this problem is to combine ICB with other anticancer therapies in order to turn cold tumors into hot ones [12].”
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“However, in many patients receiving the same treatment, the difference in the TIME of "cold" and "hot" tumors results in a very low objective response rate in "cold" tumor patients [6,7].”
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“Inhibiting HMGB2 in two cell types may “turn cold tumors hot,” diminishing the immunosuppressive immune microenvironment ( 43 ).”
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“Tuning cold tumors into hot tumors is promising to improve the therapeutic effect of immune checkpoint inhibitors [188,189].”
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Metadata
- Authors
- Zhang, J., Huang, D., Saw, P. E., & Song, E.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- Saw, Phei Er
- Song, Erwei
- Venue
- Trends in Immunology
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 43
- Issue
- 7
- Pages
- 523-545
- ISSN
- 1471-4906 (ISSN-L)
- OpenAlex
- W4281490788
- Cited by
- 534
- References
- 189
- Citations by year
- 2026: 72 · 2025: 145 · 2024: 162 · 2023: 133 · 2022: 22
- FWCI
- 14.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Trends in Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81621004, 81720108029, 81930081, 91940305, 92159303)
- Guangdong Science and Technology Department (2020B1212030004, 2020B1212060018)
- Guangzhou Municipal Science and Technology Bureau (20212200003)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cold tumors, immune evasion, immune checkpoint blockade, tumor microenvironment, immune regulation, biomarkers, combination immunotherapy, solid tumors
- MeSH terms
- Humans, Immunity, Immunotherapy, Neoplasms, Tumor Microenvironment
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