Targeting Innate Immunity in Cancer Therapy
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Updated: Nov 17, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Srikrishnan Rameshbabu1, Brian W Labadie1, Anna Argulian1
1Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Abstract:
The majority of current cancer immunotherapy strategies target and potentiate antitumor adaptive immune responses. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, with an aggregate response rate of approximately 20% to date across all malignancies. The success of therapeutic inhibition of programmed death protein 1 (PD-1), protein death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with immune checkpoint inhibitors (ICI) has been limited to "hot" tumors characterized by preexisting T cell infiltration, whereas "cold" tumors, which lack T cell infiltration, have not achieved durable benefit. There are several mechanisms by which "cold" tumors fail to generate spontaneous immune infiltration, which converge upon the generation of an immunosuppressive tumor microenvironment (TME). The role of the innate immune system in tumor immunosurveillance and generation of antitumor immune responses has been long recognized. In recent years, novel strategies to target innate immunity in cancer therapy have emerged, including therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs); the DNA sensing cGAS/STING pathway; nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRP3; and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). In addition, therapeutic modulation of key innate immune cell types, such as macrophages and natural killer cells, has been investigated. Herein, we review therapeutic approaches to activate innate immunity within the TME to enhance antitumor immune responses, with the goal of disease eradication in "cold" tumors. In addition, we discuss rational immune-oncology combination strategies that activate both innate and adaptive immunity, with the potential to enhance the efficacy of current immunotherapeutic approaches.
Insights
Cancer immunotherapies often fail in "cold" tumors. Activating innate immunity and combining it with adaptive strategies may overcome this, enhancing cancer treatment efficacy for more patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Current cancer immunotherapies, like immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4, show limited efficacy (approx. 20% response rate) primarily in
- hot
- tumors with T cell infiltration, leaving
- cold
- tumors largely untreated.
- Cold tumors develop an immunosuppressive tumor microenvironment (TME), hindering spontaneous immune responses and T cell infiltration.
Purpose of the Study:
- To review novel therapeutic strategies aimed at activating innate immunity within the TME.
- To explore approaches for enhancing antitumor immune responses, particularly in
- cold
- tumors.
- To discuss rational combination strategies that synergize innate and adaptive immunity for improved cancer treatment outcomes.
Main Methods:
- Review of therapeutic approaches targeting innate immune pathways, including pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), cGAS/STING, NLRs (e.g., NLRP3), and RIG-I-like receptors (RLRs).
- Investigation of therapeutic modulation of innate immune cells such as macrophages and natural killer (NK) cells.
- Analysis of combination immunotherapies integrating innate and adaptive immune activation.
Main Results:
- Emerging strategies focus on stimulating innate immunity to overcome the immunosuppressive TME in
- cold
- tumors.
- Targeting PRRs and modulating innate immune cells shows promise for enhancing antitumor immunity.
- Combination therapies activating both innate and adaptive immunity are being explored to improve overall treatment efficacy.
Conclusions:
- Activating innate immunity is a promising strategy to enhance antitumor responses in previously resistant
- cold
- tumors.
- Combining innate immune activation with adaptive immune strategies, such as ICIs, holds potential for broader and more durable cancer treatment benefits.
- Further research into innate immune-oncology combinations could significantly improve patient outcomes across various malignancies.
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