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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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Cites
1 retracted
Kamiya, A., Hayama, Y., Kato, S., Shimomura, A., Shimomura, T., Irie, K., Kaneko, R., Yanagawa, Y., Kobayashi, K., & Ochiya, T. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0430-3 · Cited by 287
RetractedHallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Oncology meets immunology: the cancer-immunity cycle.
Chen, D. S., & Mellman, I. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.012 · Cited by 6,929
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609
The Immune Landscape of Cancer
Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Ou Yang, T.-H., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.023 · Cited by 5,870
Self-citationGut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillère, R., Fluckiger, A., Messaoudene, M., Rauber, C., Roberti, M. P., et al. (2018) · Science · doi:10.1126/science.aan3706 · Cited by 5,671
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., et al. (2018) · Nature · doi:10.1038/nature25501 · Cited by 5,400
Elements of cancer immunity and the cancer–immune set point
Chen, D. S., & Mellman, I. (2017) · Nature · doi:10.1038/nature21349 · Cited by 5,352
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., et al. (2018) · Science · doi:10.1126/science.aan4236 · Cited by 4,812
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Flagged first, then by citations
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Items 201–300 of 544
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Jungcharoen, P., Thivakorakot, K., Thientanukij, N., Kosachunhanun, N., Vichapattana, C., Panaampon, J., & Saengboonmee, C. (2024) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2024.00220 · Cited by 13
Tertiary lymphoid structures and their therapeutic implications in cancer
Chen, X., Wu, P., Liu, Z., Li, T., Wu, J., Zeng, Z., Guo, W., & Xiong, W. (2024) · Cellular Oncology · doi:10.1007/s13402-024-00975-1 · Cited by 11
“As a biomarker, the amalgamation of TLSs with other biomarkers holds promise for achieving enhanced TLSs have emerged as valuable biomarkers [3, 77], and their prognostic significance has been investigated across various tumor types.”
DHDH-mediated D-xylose metabolism induces immune evasion in triple-negative breast cancer
Wu, H., Gong, Y., Ling, Y.-X., Wu, S., Ji, P., Zhao, Q., He, L., Shao, Z., Jiang, Y., & Liu, G. (2024) · Med · doi:10.1016/j.medj.2024.10.012 · Cited by 11
Yang, J., Chen, M., Li, R., Sun, Y., Ye, P., Fang, K., Wang, C., Shi, S., & Dong, C. (2025) · Nanoscale · doi:10.1039/d4nr03054k · Cited by 12
Wu, Q., Xia, Y., Xiong, X., Duan, X., Pang, X., Zhang, F., Tang, S., Su, J., Wen, S., Mei, L., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1169608 · Cited by 11
Salawu, A., Wang, B. X., Han, M., Geady, C., Heirali, A., Berman, H. K., Pfister, T. D., Hernando‐Calvo, A., Al-Ezzi, E. M., Stayner, L.-A., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1137 · Cited by 13
Luo, G., Wen, Y., Wang, M., Wang, H., Li, D., Liao, M., Zeng, D., Luo, S., Niu, L., Sun, T., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2413946122 · Cited by 10
Shen, X., Zhang, J., Ou, J., Bai, Z., Liu, T., Zhang, K., Zhu, K., Wang, J. Q., Wang, C., Zhang, Q., et al. (2025) · Advanced Science · doi:10.1002/advs.202512355 · Cited by 10
Self-citationYang, K., Pan, Y., Huang, X., Bai, X., Liu, X., Zhang, M., Wei, Y., Jiang, T., & Zhang, G. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1661503 · Cited by 12
“…2023; Wang L. et al., 2023; Wang Q., 2023; Wang et al., 2024; Wang XH., 2023; Wang, 2021; Xiao et al., 2022; Yang, 2023; Yao, 2023; Zhang J., 2023; Zhang, 2022; Zhao et al., 2023; Zhao, 2024; Zhou, 2023; Zhu, 2024; Cao et al., 2024; Cao, 2023; Huang et al., 2024; Ye and Fang, 2022; Yu D. et al.,…”
Tao, H., Mao, K., Zhang, Z., Wei, W., Huang, X., Chen, Y., Mei, S., & Tian, X. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.108020 · Cited by 12
Engineered Probiotics Remodel the Tumor Immune Microenvironment
Jiang, Y., Ye, Y., Wang, H., Li, Y., He, Y., Ran, H., Li, X., Xu, C., Lu, W., Tian, H., et al. (2025) · ACS Nano · doi:10.1021/acsnano.5c13557 · Cited by 11
Gastrointestinal cancer: molecular pathogenesis and targeted therapy
Jin, Y., He, X., & Wu, Y. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00361-9 · Cited by 13
“These microbial communities and their metabolites (e.g., short-chain fatty acids) can enhance immune cell activity and infiltration, thereby sustaining the “hot” state of the TME [227].”
An Immune-privileged niche mediates immunotherapy resistance in esophageal carcinoma
Wan, L., Li, B., Ma, T., Wang, M., Xie, F., Ge, H., Xiao, Z., Chen, X., Meng, L., Zhang, L., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-013959 · Cited by 10
Song, L., Wang, B., Cai, J., Zhang, P., Chen, S., Zhou, Z., & Dai, Z. (2024) · British Journal of Cancer · doi:10.1038/s41416-023-02463-z · Cited by 10
Normanno, N., Caridi, V., Fassan, M., Avallone, A., Ciardiello, F., & Pinto, C. (2024) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2024.00231 · Cited by 10
Feng, S., Zhang, Y. X., Wang, Y., Gao, Y., & Song, Y. (2024) · Chemistry - A European Journal · doi:10.1002/chem.202402485 · Cited by 10
Mielcarska, S., Kot, A., Kula, A., Dawidowicz, M., Sobków, P., Kłaczka, D., Waniczek, D., & Świętochowska, E. (2025) · Cells · doi:10.3390/cells14070530 · Cited by 11
“These tumors also demonstrate limited responsiveness to immune checkpoint blockade (ICB) therapies [62].”
Lactylation: A new direction for tumor-targeted therapy
Deng, D., Luo, Y., Hong, Y., Ren, X., Zu, X., & Feng, J. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189399 · Cited by 13
Radiotherapy plus immune checkpoint inhibitor in prostate cancer
Li, T., Qian, X., Liu, J., Xue, F., Luo, J., Yao, G., Yan, J., Liu, X., Xiao, B., & Li, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1210673 · Cited by 10
“These tumors are called “Cold” tumors, tumors with a specific tumor microenvironment which causes the failure of ICI therapy (12).”
BackgroundLysine-specific demethylase 1 as a therapeutic cancer target: observations from preclinical study
Johnson, J. D., Alejo, S., Jayamohan, S., & Sareddy, G. R. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2288277 · Cited by 9
“In contrast, ‘hot tumors’ are characterized by the infiltration of CD8 + cytotoxic T cells, which is associated with a favorable prognosis [33].”
BackgroundChang, L.-C., Chin, Y., Wu, P., Wei, Y., Wu, H., Cheng, T.-Y., Yin-fen, L., Huang, C., & Su, W. (2023) · Nano Today · doi:10.1016/j.nantod.2023.102070 · Cited by 9
Gao, S., Hou, Y., Xu, Y., Li, J., Zhang, C., Jiang, S., Tu, W., Liu, L., Tu, W., Yu, B., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116853 · Cited by 9
Ultrasound-Driven Nanomachine for Enhanced Sonodynamic Therapy of Non-Small-Cell Lung Cancer
Ping, W., Zhang, X., Zeng, H., Zhu, T., Zhang, N., & Yan, Q. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c11546 · Cited by 9
Hu, C., Jiang, Y., Chen, Y., Wang, Y., Wu, Z., Zhang, Q., & Wu, M. (2024) · Cancers · doi:10.3390/cancers16213657 · Cited by 9
Sun, W., Huang, S., Sun, Z., Zhao, Q., Li, J., Wen, B., Liu, J., Deng, G., & Sun, C. (2025) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c17804 · Cited by 9
Pancreatic cancer subtyping - the keystone of precision treatment
Fan, Z., Xiao, Y., Du, Y., Zhang, Y., & Zhou, W. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1563725 · Cited by 9
“Although this therapy has bene fi ted some patients with solid tumors (102), a substantial proportion of “ cold ” tumors show limited response to ICB therapy (103), possibly due to the diversity of immune evasion mechanisms.”
Wang, X., & Hu, Y. (2025) · Oncology Letters · doi:10.3892/ol.2025.15049 · Cited by 9
“In tumor immunology, tumors are categorized as ‘cold’ or ‘hot’ based on their immune microenvironment (30).”
Current advances and future directions of combined ICIs and TILs in solid tumors
Wang, Y., Ding, Q., & Wei, J. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.218145 · Cited by 9
Yin, X., Wu, J., Xu, M., Tian, T., Zhu, L., Wang, J., Dai, X., Yang, X., Qian, J., Wang, W., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02502-8 · Cited by 9
“9).”
Effector Immune Cell Deployment: a revolutionized concept in cancer immunotherapy
Su, S. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2184-6 · Cited by 9
“Therefore, EICD not only provides a theoretical basis for a holistic approach in assessing anti-tumor immunity, it is the first concept to fully reflect tumor immunophenotyping; an important feature for predicting prognoses and guiding immunotherapy regimens (Zhang et al., 2022)(Figure 1).”
BackgroundWu, F., Ning, H., Sun, Y., Wu, H., & Lyu, J. (2023) · The Aging Male · doi:10.1080/13685538.2023.2183947 · Cited by 9
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BackgroundSubtype and prognostic analysis of immunogenic cell death-related gene signature in prostate cancer
Kang, Z., Sun, J., Lin, F., Huang, X., Huang, Q., Chen, D., Zheng, Q., Xue, X., Xu, N., & Wei, Y. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1160972 · Cited by 9
Zhou, F., Li, X., Jia, K., Li, F., Xue, X., Liu, J., Qu, J., & Liu, R. (2023) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2023.106581 · Cited by 9
Huang, M., Xia, Y., Li, K., Shao, F., Feng, Z., Li, T., Azin, M., & Demehri, S. (2023) · Journal of Clinical Investigation · doi:10.1172/jci166494 · Cited by 9
“However, only a subset of cancers with high TMB and neoantigen load show a durable response to immunotherapy (13).”
BackgroundMasuda, Y., Nakayama, Y., Shimizu, R., Naito, K., Miyamoto, E., Tanaka, A., & Konishi, M. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121453 · Cited by 8
Ou, Q., Lu, K., Cai, G., Lai, Z., Lin, R., Huang, H., Zeng, D., Wang, Z., Luo, B., Ouyang, W., et al. (2024) · MedComm – Future Medicine · doi:10.1002/mef2.89 · Cited by 8
Emerging Cationic Nanovaccines
Carmona‐Ribeiro, A. M., & Pérez-Betancourt, Y. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16111362 · Cited by 8
“Cancer immunotherapies seldom produce favorable outcomes in patients since most types of cancer can suppress antigen presentation, dendritic cell maturation and/or activation and infiltration of T lymphocytes in the tumor [183,184].”
Huo, T., Zhu, B., Shan, X., Song, J., Wang, Z., Zhou, J., Zhang, X., Bai, Y., Liu, C., Zhao, Y., et al. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.159871 · Cited by 8
Self-citationPalade, J., Alsop, E., Tang, N., Antone, J., Paredes, D., Halder, T., Soldi, R., Bargenquast, T., Schwartz, G., Finholt, J. P., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1633010 · Cited by 8
Wu, Z., Jiang, G., Jiang, Z., Zhou, Y., Ji, Y., Wang, L., Li, P., Liu, S., Zhang, X., & Liu, T. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03950-6 · Cited by 8
“The hallmark events of ICD include calreticulin (CRT) exposure, high-mobility group box 1 (HMGB1) release, and ATP secretion [52].”
Shin, S., Bae, G.-H., Park, J. D., Koh, E.-Y., Ko, S., Han, J., Park, C. G., Kim, D.-H., Na, K., & Park, W. (2026) · Biomaterials · doi:10.1016/j.biomaterials.2026.124002 · Cited by 8
Viral escape from NK‐cell‐mediated immunosurveillance: A lesson for cancer immunotherapy?
Momayyezi, P., Bilev, E., Ljunggren, H., & Hammer, Q. (2023) · European Journal of Immunology · doi:10.1002/eji.202350465 · Cited by 8
“Furthermore, the dichotomy between immunosuppressive environments of cold tumors and immune-responsive hot tumors is a key difference between antitumor responses and viral infections and poses a central obstacle in cancer therapy [104].”
BackgroundGómez‐Valenzuela, F., Wichmann, I. A., Suárez, F., Kato, S., Ossandón, E., Hermoso, M. A., Fernández, E. A., & Cuello, M. A. (2023) · Cancers · doi:10.3390/cancers16010080 · Cited by 9
“A higher abundance of tumor-infiltrating lymphocytes (TILs) is associated with a better prognosis in HGSOC [3].”
BackgroundYamasaki, S., Shimizu, K., & Fujii, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1345037 · Cited by 8
“There are several cancers, such as PCa, pancreatic, ovarian and breast cancers, in which both NK and T cells are dysfunctional from a clinical standpoint (19).”
BackgroundShifting cold to hot tumors by nanoparticle-loaded drugs and products
Ahmad, I., Altameemi, K. K. A., Hani, M. M., Ali, A. M., Shareef, H. K., Hassan, Z. F., Alubiady, M. H. S., Al‐Abdeen, S. H. Z., Shakier, H. G., & Redhee, A. H. (2024) · Clinical & Translational Oncology · doi:10.1007/s12094-024-03577-3 · Cited by 9
“These tumors are often responsive to immunotherapy and other therapy agents, and have a better prognosis compared to cold tumors [3].”
Discovery and Evaluation of TLR-Targeted Immune Agonists
Chernyak, N., Bhagwat, B., Naravula, S., Chen, Y., Solban, N., Zhang, F., Kofman, E., Raoufi, F., Dang, X., Bao, J., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00804 · Cited by 8
Wang, Y., Gao, S., Xu, Y., Tang, Z., & Liu, S. (2023) · Scientific Reports · doi:10.1038/s41598-023-30927-y · Cited by 8
Deng, S., Wang, J., Hu, Y., Sun, Y., Yang, X., Zhang, B., Deng, Y., Wei, W., Zhang, Z., Wen, L., et al. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02413-8 · Cited by 8
“The inflamed TME is characterized by the infiltration of lymphocytes and specifically the presence of an abundance of tumor-infiltrating lymphocytes (TILs) [28].”
BackgroundLuo, J., Ng, W., Liu, Y., Wang, L., Gong, C., Zhou, Y., Cheng, F., Zhu, S., & Yao, C. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03706-5 · Cited by 7
Hsiehchen, D., Elliott, A., Xiu, J., Seeber, A., El‐Deiry, W. S., Antonarakis, E. S., Graff, S. L., Hall, M. J., Borghaei, H., Hoon, D. S. �., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.10.017 · Cited by 7
A lyophilizable LNP vaccine enables STING-reinforced postoperational adjuvant immunotherapy
Yang, Y., Guo, J., Qi, J., Deng, W., Hu, J., Hasan, M. W., Deng, F., Zhou, Y. L., Song, Z., Deng, W., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03445-4 · Cited by 10
“However, in “immunologi-cally cold tumors”, the paucity of immune cells infiltration limits the efficacy of iCBT in a subset of patients [4, 5].”
Chen, J., Ma, F., Chen, Y., Xu, M., Zhang, Y., Wang, S., Liu, H., Xu, L., Liu, Y., Ma, R., et al. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.06.010 · Cited by 10
“…CTLs-associated chemokine secretion in the TME is frequently compromised by intrinsic tumor immunosuppressive mechanisms, including low immunogenicity of tumor cells, impaired antigen presentation, and defective T cell priming, leading to low chemotactic ability of circulating T cells [10 – 12].”
Du, X., Zhang, Y., Gu, B., Yang, Z., Xu, X., Peng, H., Song, S., & Yang, Z. (2025) · Journal of Materials Chemistry B · doi:10.1039/d5tb00322a · Cited by 7
Huang, C., Wang, H., Yang, X., Wang, H., Li, W., Zhang, L., & Zhu, D. (2025) · Nano Letters · doi:10.1021/acs.nanolett.5c02670 · Cited by 7
Zhang, J., Fan, Y., Wang, Y., Wang, X., Wang, Z., Liu, H., Liu, C., Wang, Z., & Luo, D. (2025) · Nano Energy · doi:10.1016/j.nanoen.2025.111431 · Cited by 8
Self-citationPositive and negative roles of myeloid cells in cancer immunotherapy
Žák, J., & Varner, J. A. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012743 · Cited by 7
Cho, K. J., Cho, Y., & Kim, J. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122752 · Cited by 7
“Food and Drug Administration (FDA), are representative immunotherapeutics that reprogram these “cold” tumors to “hot” tumors that are not only characterized by abundant cytotoxic CD8+ T cells (CTLs) and natural killer (NK) cells, but are also responsive to these immune cells [2,3].”
BackgroundDo macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?
Knudsen-Clark, A. M., Cazarin, J., & Altman, B. J. (2023) · F1000Research · doi:10.12688/f1000research.129863.1 · Cited by 7
Overcoming melanoma resistance to immune checkpoint blockade therapy using nano-strategies
Ding, Y., Liu, C., Wu, Y., & Fu, F. (2023) · Biomedical Technology · doi:10.1016/j.bmt.2023.03.003 · Cited by 7
Jia, D., Zhao, S., Liu, H., Zhan, X., Zhou, Z., Lv, M., Tang, X., Guo, W., Li, H., Sun, L., et al. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.132058 · Cited by 7
Cao, L., Tang, D., Yu, Z., Shen, Y., Wang, Y., Li, Y., Chen, J., Liu, Z., Yin, J., Xiao, H., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202403225 · Cited by 7
Andersson, H., Sobti, A., Jimenez, D. G., de Coaña, Y. P., Ambarkhane, S., Hägerbrand, K., Smith, K. E., Lindstedt, M., & Ellmark, P. (2023) · Cells · doi:10.3390/cells12192365 · Cited by 7
“…approved indications where ICI therapies have Cells 2023 , 12 , 2365 2 of 14 limited efficacy, as well as expand the scope of eligible immunotherapy indications [1], by making the tumors more inflamed via pathways such as type I interferon [8], effectively turning immunological cold tumors hot [9].”
BackgroundPoudel, Y. B., He, L., Cox, M., Zhang, Q., Johnson, W. L., Cong, Q., Cheng, H. W., Chowdari, N. S., Tarby, C. M., Donnell, A. F., et al. (2024) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00455 · Cited by 7
Yumoto, S., Horiguchi, H., Kadomatsu, T., Horino, T., Sato, M., Terada, K., Miyata, K., Moroishi, T., Baba, H., & Oike, Y. (2024) · Cancer Science · doi:10.1111/cas.16348 · Cited by 6
“13,14 However, several studies indicate that even tumors with high CD8 + T cell infiltration may not respond to ICI, 15–17 suggesting that T cells play a key role but are not sufficient for ICI responsiveness.”
Yin, Y., & Luo, M. (2025) · Discover Oncology · doi:10.1007/s12672-025-02524-0 · Cited by 6
Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity
Liu, T., Zhang, M., Farsh, T., Li, H., Kishishita, A., Barpanda, A., Leung, S. G., Zhu, J., Jung, H., Hua, J. T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60745-x · Cited by 6
“Immune-cold tumors are characterized by low neoantigen expression and immune cell in fi ltration, resulting in a less effective T-cell mediated immune response against the tumor 13 .”
Yan, F., Jing, C., Duan, S., Xia, Y., Xiao, R., Shao, S., Xiao, Z., Chen, W., & Li, C. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c00333 · Cited by 6
Nan, L., Qin, Y., Huang, X., Pan, M., Wang, X., Lv, Y., Sørensen, A., Kang, X., Ling, H., & Zhang, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157567 · Cited by 6
“Yet, numerous studies have shown that these agents are significantly less effective against immunologically “cold” tumours [36].”
Self-citationChen, Y., & Tang, D. (2025) · Future Oncology · doi:10.1080/14796694.2025.2558287 · Cited by 6
Hobson, J. N., Grams, M. P., Gicobi, J. K., Wigle, D. A., Kottschade, L. A., Durham, L. A., Corbin, K. S., Dong, H., Markovic, S. N., & Park, S. S. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1697902 · Cited by 6
“These effects may increase lymphocytic in fi ltration, converting a cold tumor into a hot tumor and overcoming immune exclusion, thereby improving ICI ef fi cacy (26).”
Ma, C., Teoh, H. K., Zhao, Y., Wang, Y., Zhao, J., Liu, Y., Zhao, C., & Ong, H. T. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1760782 · Cited by 7
“…for subtype-speci fi c responses: this entails optimizing ICB combinations with PARP inhibitors or T cell engagers for TNBC, while exploring combinations with CDK4/6 or PI3K inhibitors-known for their immunomodulatory effects to convert HR + /HER2 – “ cold ” tumors into “ hot ” ones (73, 165).”
Kleef, R., Dank, M., Herold, M., Ágoston, E. I., Lohinszky, J., Martinek, E., Herold, Z., & Szász, A. M. (2023) · Scientific Reports · doi:10.1038/s41598-023-47802-5 · Cited by 6
“Of the IMTs, locoregional mEHT (median: 16; range: 2–51) and high-dose vitamin C treatment (median: 15; range: 2–38) were used the most often, followed by low-dose ICIs (median: 3; range: 1–12) and WBH (median: 6; range: 1–25) treatments.”
InfluentialPaired Box 5 (PAX5) Gene Has Diagnostic and Prognostic Potential in Nasopharyngeal Carcinoma
Ye, J., Huang, X., Qin, W., Liang, P., Zhao, J., Ye, Y.-F., Ji, H., Peng, X., Liang, Y., & Cai, Y. (2024) · International Journal of General Medicine · doi:10.2147/ijgm.s442835 · Cited by 6
Li, H., Fan, J., Ma, J., Qiao, L., Sha, T., & Ma, B. (2024) · Archives of Medical Science · doi:10.5114/aoms/187080 · Cited by 7
“Notably, the infiltration of CD4+ T cells is recognized as a key factor in the efficacy of immunotherapy [3].”
Wang, H. R., Zhang, Y., Mo, Y., Zhang, Z., Chen, R., Lu, X. B., & Huang, W. (2024) · Communications Biology · doi:10.1038/s42003-024-06566-y · Cited by 6
“Studies revealed that the major predictive factor of these ‘ cold ’ tumors is the lack of suf fi cient T cell in fi ltration and a T cell-in fl amed gene expression pro fi le in tumors 39,40 .”
Tang, L., Wang, D., Hu, T., Lin, X., & Wu, S. (2024) · Cancer Drug Resistance · doi:10.20517/cdr.2024.77 · Cited by 6
Aspord, C., Jílková, Z. M., Bonadona, A., Gerster, T., Lesurtel, M., Girard, É., Saas, P., & Decaens, T. (2024) · Transplantation · doi:10.1097/tp.0000000000005274 · Cited by 6
“6 A recent meta-analysis revealed that HOPE reduces acute cellular rejection after LT compared with SCS. 7 Altogether, although a significant number of experimental and clinical trials demonstrated that HOPE is a more physiologic method of liver preservation compared with SCS, 3,8 by reducing IRI,…”
The Two Faces of Angiopoietin‐Like Protein 2 in Cancer
Horiguchi, H., Kadomatsu, T., & Oike, Y. (2024) · Cancer Science · doi:10.1111/cas.16434 · Cited by 6
“…responders exhibit a “hot tumor” phenotype, characterized by T lymphocyte infiltration, while non-responders often exhibit “cold tumor” phenotypes, characterized by low immunogenicity, deficient antigen presentation, impaired T cell trafficking, or an immunosuppressive tumor microenvironment [51].”
Wang, M., He, Q., Chen, Z., & Qin, Y. (2025) · Scientific Reports · doi:10.1038/s41598-025-87444-3 · Cited by 6
“However, patients with high CMLS have more fibroblasts and M2 macrophages enriched and multiple cancer pathways activated, such as the EMT and TGF-β pathways, implying that these patients may be more consistent with a “cold tumor” phenotype 62,63 .”
Tumor evolution-targeted nanomedicineEVT
Zhang, L., Yang, J., Tang, D., Zhang, H., Ding, J., & Xiao, H. (2022) · Scientia Sinica Chimica · doi:10.1360/ssc-2022-0158 · Cited by 6
Lin, H., Pang, W.-P., Yuan, H., Kong, Y., Long, F., Zhang, R., Yang, L., Fang, Q.-L., Pan, A., Fan, X., et al. (2023) · Aging · doi:10.18632/aging.204870 · Cited by 5
Classification of Brainstem Gliomas Based on Tumor Microenvironment Status
Xiao, X., Li, X., Wang, Y., Pan, C., Zhang, P., Gu, G., Li, T., Jiang, Z., Zhang, Y., & Zhang, L. (2023) · Cancers · doi:10.3390/cancers15174224 · Cited by 6
“Meanwhile, since the TME clusters have shown their independent prognostic value, it is suggested that novel treatments that can modify the TME status may have the potential to benefit BSG patients [16,44].”
BackgroundEvolution by innovation as a driving force to improve TCR-T therapies
Schendel, D. J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1216829 · Cited by 6
“There are gradations in between these two extremes (160 – 163).”
BackgroundGong, W., Wang, Z., Wei, Y., Wang, M., Li, K., Chen, X., Huang, X., Zhou, L., Gan, Q., Xu, X., et al. (2025) · Discover Oncology · doi:10.1007/s12672-025-01943-3 · Cited by 5
“Our study demonstrated that ICB therapy stimulated the proliferation of Ts cells in peripheral blood [33].”
Mei, X., Fobian, S., IJff, M., Crezee, J., van Bochove, G. G. W., van Lonkhuijzen, L. R. C. W., Mom, C. H., van den Broek, C. B. M., Köster, J., de Koning, W., et al. (2025) · International Journal of Gynecological Cancer · doi:10.1016/j.ijgc.2025.101924 · Cited by 5
Jiang, L., Wu, T., Qu, X., Li, S., Jiang, Q., Ren, T., Liang, J., Ding, Y., Hua, K., Tang, Z., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03500-0 · Cited by 5
“The ICBs efficiency in cold tumors are always worse than that in hot tumors [32].”
A MnO2-based tumor-seeking nanoplatform for enhanced chemoimmunotherapy against 4T1 breast cancer
Gong, T., Wang, X., Liu, Z., Li, P., Li, P., Guo, Y., Han, M., & Wang, X. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.102000 · Cited by 5
“STING agonists activate immune response mainly by enhancing antigen presentation [45].”
Lu, J., Chan, T. T.-H., Wang, Y., Wang, J., Xiong, Z., Li, J., Zhang, Y., Wang, H., Chen, J., Yang, W., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3854 · Cited by 5
Xing, Y., Zhou, Y., Wang, R., Chen, J., Yang, L., Meng, X., Wang, J., Ouyang, Q., Zhao, J., Chen, F., et al. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.08.003 · Cited by 6
Self-citationChen, Q., Wang, W., He, X., Wang, C., Guo, H., & Ou, C. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.218034 · Cited by 7
Gao, Y., Xia, Y., Li, J., Lai, Y., Yin, S.-L., Lin, J., Yu, D. Y., Huang, S., Lu, F., Wang, W., et al. (2025) · Cellular Oncology · doi:10.1007/s13402-025-01124-y · Cited by 5
Li, X., Wang, Z., Mao, S., Zhao, Y., Ye, J., Liang, B., Peng, J., Xie, X., Pan, J., Xiao, C., et al. (2026) · iScience · doi:10.1016/j.isci.2025.114607 · Cited by 6
“Zhang et al. 19 ; Liang et al. 20 ; Zhao et al. 21 MDSCs depleting amino acids, producing NO/ROS, and promoting Treg expansion via TGF-β /IL-10.”
Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice
Zhang, X., Gao, Y., Hu, W., Liang, Y., Yin, X., Shi, X., Li, H., Liao, H., Guo, J., Yu, X., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70876-4 · Cited by 6
Peng, J., Yang, Q., Jiang, H., Wang, Y., Liu, Q., Xiao, Y., & Qian, Z. (2023) · Nano Today · doi:10.1016/j.nantod.2023.102087 · Cited by 5
Msaouel, P., & Sheth, R. A. (2024) · Journal of Vascular and Interventional Radiology · doi:10.1016/j.jvir.2023.09.035 · Cited by 5
Tumor stroma-derived ANGPTL2 potentiates immune checkpoint inhibitor efficacy
Horiguchi, H., Kadomatsu, T., Yamashita, T., Yumoto, S., Horino, T., Sato, M., Terada, K., Miyata, K., Ichigozaki, Y., Kimura, T., et al. (2024) · Cancer Gene Therapy · doi:10.1038/s41417-024-00757-9 · Cited by 5
Molecular subtypes and prognostic factors of lung large cell neuroendocrine carcinoma
Liu, T., Chen, X., Mo, S., Zhou, T., Ma, W., Chen, G., Chen, X., Shi, M., Yang, Y., Huang, Y., et al. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-292 · Cited by 5
“High CD3 + TIL, CD8 + TIL, and CD68 + TIM were associated with good prognosis in cancers (58-62), and high immune cell infiltration with anti-tumor effect in tumor tissue has been regarded as a hot tumor microenvironment (63,64).”
BackgroundLin, Q., Wang, Z., Wang, J., Xu, M., Zhang, X., Sun, P., & Yuan, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1509658 · Cited by 5
Li, L., Wang, G., Xue, B., Li, X., Wang, J., Wang, W., Liu, C., Li, C., & Zheng, X. (2025) · ACS Materials Letters · doi:10.1021/acsmaterialslett.5c00097 · Cited by 5
Hayes, A. J., Davies, E. J., Wilkinson, M., Smith, H. G., Nenclares, P., Lund, T., Lärkeryd, A., Appleton, E. S., Patin, E. C., Pedersen, M., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012446 · Cited by 5
“13 Oncolytic virotherapy (OV) is a prime candidate for such an approach.”
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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