“Cold” tumors are generally characterized by insufficient tumor antigen presentation, limited effector T-cell infiltration, and pronounced local immunosuppression, resulting in relatively poor responses to immune checkpoint blockade. “Hot” tumors exhibit more active inflammatory responses, abundant tumor-infiltrating lymphocytes, and a more complete cancer-immunity cycle. Enhancing tumor antigen release, activating innate immune sensing, promoting T-cell recruitment and tissue infiltration, and relieving immunosuppression can shift the tumor microenvironment from an immune-low state toward immune activation.

Keywords: cold tumors; hot tumors; tumor immunity; cGAS–STING; immunogenic cell death; T-cell infiltration; immune checkpoints; tumor microenvironment

1 Overview of “Cold” and “Hot” Tumors

1.1 Immune Characteristics of “Hot” Tumors

“Hot” tumors generally contain relatively high levels of infiltrating CD8⁺ T cells and show enhanced inflammatory and chemotactic signals, including type I interferons, IFN-γ, CXCL9, and CXCL10. Tumor antigens can be captured, processed, and presented by dendritic cells, while primed tumor-specific T cells enter tumor tissues and recognize target cells. Persistent immune selection pressure may also induce negative-feedback mechanisms such as PD-L1 upregulation, making these tumors more likely to benefit from immune checkpoint blockade targeting PD-1/PD-L1 and related pathways.

1.2 “Cold” Tumors Do Not Represent a Single Immune State

(1) Immune-Desert Tumors

Immune-desert tumors lack effective T-cell priming and show little infiltration of effector lymphocytes within either the tumor parenchyma or surrounding tissues. This state may involve insufficient tumor antigens, abnormal antigen processing and presentation, impaired dendritic cell function, and inadequate innate immune sensing.

(2) Immune-Excluded Tumors

Immune-excluded tumors are not completely devoid of T cells. Instead, T cells are mainly distributed within the tumor stroma or invasive margin and fail to enter cancer cell-rich regions. Abnormal tumor vasculature, a dense extracellular matrix, enhanced TGF-β signaling, and myeloid immunosuppression can create spatial and functional barriers that restrict T-cell entry into the tumor parenchyma.

1.3 “Hot” Tumors May Still Exhibit Immune Dysfunction

Some tumors contain substantial T-cell infiltration but also show persistent antigen stimulation, enhanced inhibitory signaling through PD-1/PD-L1, LAG-3, and TIM-3, and immunosuppressive mechanisms involving regulatory T cells, myeloid-derived suppressor cells, and adenosine metabolism. Tumor-infiltrating T cells may consequently become exhausted or functionally restricted. The “cold–hot” classification primarily reflects the overall inflammatory and infiltrative characteristics of the tumor immune microenvironment and cannot independently serve as an absolute predictor of immunotherapy efficacy.

2 Mechanisms Underlying Immune-Low Tumor States

2.1 Insufficient Tumor Antigen Generation and Presentation

Effective antitumor immunity initially depends on tumor antigens that can be recognized by the immune system. Low tumor mutational burden, reduced antigen expression, and immunoediting can decrease tumor immunogenicity. Abnormalities in β2-microglobulin, the MHC-I antigen-presentation system, and associated antigen-processing mechanisms can further impair the display of tumor antigens on the cell surface and reduce the efficiency with which cytotoxic T cells recognize tumor cells.

2.2 Insufficient Innate Immune Sensing

Tumor-derived DNA entering the cytosol can be recognized by cGAS, which catalyzes the production of 2′,3′-cGAMP and subsequently activates STING–TBK1–IRF3 signaling and type I interferon production. Type I interferons contribute to dendritic cell maturation, antigen cross-presentation, and T-cell priming. Some tumors maintain low-inflammatory and immune-low states by reducing cGAS–STING pathway activity, enhancing cGAMP degradation, or suppressing interferon signaling.

2.3 Restricted T-Cell Recruitment and Tumor Infiltration

Activated T cells migrate toward tumor tissues in response to chemotactic signals such as CXCL9, CXCL10, and CXCL11. Some immune-low tumors lack effective chemokine expression and exhibit VEGF-driven abnormal vasculature in which endothelial adhesion molecule expression and vascular permeability are unfavorable for lymphocyte transendothelial migration. Cancer-associated fibroblasts and a dense extracellular matrix can create additional spatial barriers that restrict T-cell entry into the tumor parenchyma.

2.4 The Immunosuppressive Tumor Microenvironment

Regulatory T cells, PMN-MDSCs, and immunosuppressive tumor-associated macrophages can inhibit effector T cells through TGF-β, IL-10, ARG1, ROS, and related pathways. CD39–CD73-mediated conversion of extracellular ATP into adenosine, VEGF-driven abnormal vasculature, hypoxia, and lactate accumulation can further reduce T-cell activity, preventing effector lymphocytes that have already entered tumor tissues from maintaining sustained antitumor functions.

3 Key Mechanisms for Converting the Tumor Immune Microenvironment from “Cold” to “Hot”

3.1 Enhancing Tumor Antigen Release

Radiotherapy, certain chemotherapies, oncolytic viruses, and other interventions capable of inducing immunogenic cell death (ICD) can promote tumor antigen release. These treatments may also induce damage-associated molecular pattern changes, including ATP release, HMGB1 release, and calreticulin exposure. Such alterations increase the immunogenicity of dying tumor cells and provide a basis for dendritic cell-mediated tumor antigen uptake and subsequent T-cell priming.

3.2 Activating Innate Immunity and Dendritic Cells

Cytosolic DNA–cGAS–STING signaling and pattern-recognition receptors such as TLRs convert tumor-derived nucleic acid signals into type I interferon and inflammatory responses. After receiving maturation signals, dendritic cells capture, process, and cross-present tumor antigens and prime tumor-specific CD8⁺ T cells in tumor-draining lymph nodes, helping establish adaptive antitumor immunity within immune-desert microenvironments.

3.3 Promoting Effector T-Cell Recruitment and Tissue Infiltration

Type I interferon- and IFN-γ-associated signaling can promote the expression of chemokines such as CXCL9 and CXCL10 and enhance the migration of CXCR3⁺ effector T cells toward tumor tissues. Improving abnormal tumor vasculature, reducing VEGF signaling, and weakening TGF-β-associated stromal barriers may further promote T-cell transendothelial migration and entry into the tumor parenchyma, shifting immune-excluded tumors toward an immune-infiltrated state.

3.4 Restoring the Effector Function of Tumor-Infiltrating T Cells

Increased T-cell infiltration does not necessarily produce effective antitumor immunity. Persistent antigen stimulation can induce inhibitory receptors such as PD-1, TIM-3, and LAG-3, while tumor cells and myeloid cells can further restrict T-cell function through PD-L1, adenosine, and a metabolically suppressive environment. Blocking immune checkpoints and other immunosuppressive pathways can restore the proliferation, cytokine secretion, and cytotoxic activity of tumor-infiltrating T cells.

4 Major Strategies for Converting Tumors from “Cold” to “Hot”

4.1 Inducing Immunogenic Cell Death

Radiotherapy can cause DNA double-strand breaks, micronucleus formation, and cytosolic DNA accumulation, activating cGAS–STING signaling under appropriate conditions. Certain chemotherapeutic agents, including anthracyclines and Oxaliplatin, can also induce tumor cell death with immunogenic characteristics. Tumor antigen release and exposure of damage-associated signals can jointly promote dendritic cell recruitment and antigen presentation, establishing a more favorable immune basis for subsequent immune checkpoint blockade.

4.2 Activating the cGAS–STING and TLR Pathways

(1) The cGAS–STING Pathway

2′,3′-cGAMP, diABZI, and other STING agonists enhance STING–TBK1–IRF3 signaling and promote type I interferon production, helping restore innate immune sensing in tumors and local immune cells. STING activation can also promote dendritic cell maturation, CD8⁺ T-cell priming, and inflammatory chemokine expression.

(2) TLR Pathways

Pattern-recognition receptors such as TLR3, TLR7/8, and TLR9 recognize different nucleic acid signals. TLR agonists can activate dendritic cells and other innate immune cells and increase type I interferon and inflammatory cytokine production, thereby strengthening immune-priming signals in tumors with low baseline inflammation.

4.3 Remodeling Local Tumor Immunity with Oncolytic Viruses

Oncolytic viruses can selectively replicate in tumor cells or induce tumor cell lysis while releasing tumor antigens, viral nucleic acids, and inflammatory signals. Local viral infection can enhance dendritic cell activation and T-cell recruitment and alter cytokine and immune checkpoint expression within tumors, providing an immunological basis for combination with immune checkpoint blockade.

4.4 Targeting Tumor Vascular and Stromal Barriers

VEGF not only promotes tumor angiogenesis but also contributes to structurally abnormal, unevenly perfused vasculature with insufficient immune cell adhesion. Appropriate inhibition of VEGF/VEGFR signaling can promote vascular normalization and improve immune cell infiltration. Extracellular matrix remodeling mediated by TGF-β and cancer-associated fibroblasts can produce spatial T-cell exclusion, and targeting these structural barriers may increase the density of effector T cells within the tumor parenchyma.

4.5 Relieving Myeloid Immunosuppression

CXCL–CXCR2 signaling promotes the recruitment of neutrophils and PMN-MDSCs, whereas pathways such as CSF1–CSF1R contribute to the recruitment and maintenance of tumor-associated macrophages. Blocking the recruitment of protumor myeloid cells or reprogramming their functional states can reduce immunosuppressive factors such as ARG1, ROS, and IL-10 and help restore CD8⁺ T-cell infiltration and effector activity.

4.6 Combination with Immune Checkpoint Blockade

PD-1/PD-L1 blockade primarily acts on pre-existing antitumor T cells whose functions have been suppressed. Immune checkpoint inhibitors alone therefore generally have limited activity in immune-desert tumors. Combining PD-1/PD-L1 blockade with STING or TLR agonists, oncolytic viruses, radiotherapy, vascular normalization, or myeloid cell-targeted interventions can address distinct barriers involving insufficient antigen release, impaired T-cell priming, restricted infiltration, and suppression of local effector function.

5 Research Progress in Converting Tumors from “Cold” to “Hot”

5.1 T-VEC

(1) Oncolytic Virus-Mediated Immune Activation

Talimogene laherparepvec (T-VEC) is an engineered HSV-1 oncolytic virus that induces local tumor cell lysis and expresses GM-CSF. Tumor cell lysis releases antigens, while virus-derived nucleic acids and inflammatory signals further promote local innate immunity and antigen presentation, increasing immune activation within the tumor microenvironment.

(2) Immunotherapy for Melanoma

T-VEC has been used as a local treatment for unresectable melanoma and has further supported studies combining oncolytic viruses with PD-1/PD-L1 blockade. These studies demonstrate that, in addition to directly destroying tumor cells, local oncolytic therapy can contribute to systemic antitumor immunity by altering the tumor immune microenvironment and lymphocyte infiltration.

5.2 Vidutolimod

(1) TLR9 Activation

Vidutolimod (CMP-001) is a virus-like particle-based TLR9 agonist strategy that activates plasmacytoid dendritic cells and enhances type I interferon responses, promoting antigen presentation and effector T-cell recruitment.

(2) Studies in PD-1-Resistant Tumors

Vidutolimod combined with PD-1 blockade has been studied in melanoma that progressed after previous PD-1 treatment. Some patients showed increased intratumoral T-cell infiltration and antitumor responses, supporting evaluation of whether innate immune activation can restore sensitivity to immune checkpoint blockade.

5.3 BO-112

(1) Double-Stranded RNA-Mediated Innate Immune Activation

BO-112 consists of nanoplexed double-stranded RNA. Following intratumoral administration, it activates RNA-sensing innate immune pathways and induces type I interferon production, immunogenic cell death, and local inflammatory responses, allowing tumor antigen release and innate immune activation to occur simultaneously.

(2) Combination Studies with Immune Checkpoint Blockade

BO-112 has been combined with PD-1 blockade in studies involving solid tumors resistant to previous immune checkpoint therapy. These studies primarily evaluate whether local innate immune activation can increase tumor T-cell infiltration and restore sensitivity to immune checkpoint treatment.

5.4 STING Agonists

(1) Activation of STING–Type I Interferon Signaling

MIW815, MK-1454, and subsequent non-cyclic dinucleotide STING agonists have been investigated for their ability to directly activate STING, enhance type I interferon production, and promote dendritic cell function. Early intratumoral STING agonists induced local immune pharmacodynamic changes, although their antitumor activity as monotherapies remained limited.

(2) New STING Agonist Strategies

Traditional cyclic dinucleotide STING agonists are limited by intratumoral administration requirements, stability, and pharmacokinetic properties. Subsequent research has shifted toward STING agonists with improved systemic exposure, tumor-delivery capacity, or alternative molecular structures and has further explored combinations with PD-1/PD-L1 blockade and other immunotherapies.

6 Products

6.1 Products for cGAS–STING Innate Immunity Research

6.2 Products for CXCR1/2 and Myeloid Immunosuppression Research

6.3 Products for Immune Checkpoint and Type I Interferon Response Research

6.4 Products for Tumor Cell Proliferation, Death, and DNA Damage Research

The conversion of the tumor immune microenvironment from “cold” to “hot” fundamentally involves re-establishing the cancer-immunity cycle comprising tumor antigen release, innate immune sensing, T-cell priming and recruitment, infiltration into tumor tissues, and effector-mediated killing. Because the limiting stages differ substantially among tumors, mechanism-based stratification of interventions targeting antigen insufficiency, immune deserts, spatial exclusion, and local immunosuppression represents an important direction for improving immunotherapy sensitivity.

References

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[4] Demaria O, Cornen S, Daëron M, Morel Y, Medzhitov R, Vivier E. Harnessing innate immunity in cancer therapy. Nature. 2019;574:45–56.

[5] Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–1355.

[6] Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404–2411.

[7] Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–741.

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[5] mtDNA Stress and cGAS–STING/AIM2 Innate Immune Activation Mediated by CRAT Deficiency