Cancer Immunotherapy: Can Antifibrotics Unlock the Door to Cold Tumors?

Introduction

Cancer immunotherapy has revolutionized the landscape of cancer treatment, shifting the paradigm from non-specific, cytotoxic approaches to strategies that harness the body’s immune system to combat disease. Initially conceived as a last-line treatment for advanced metastatic cancers, immunotherapy has evolved into a cornerstone of first- and second-line therapies for multiple malignancies, including melanoma, lung, and bladder cancers ¹. By employing innovative techniques such as immune checkpoint inhibitors, adoptive cell therapies (e.g., CAR-T and TCR-T), and novel immunomodulatory agents, these therapies aim to overcome immune suppression and enhance immune recognition of tumor cells.

However, significant challenges remain, particularly in addressing the immune-excluded and immune-deserted tumor microenvironments (TME) that characterize so-called "cold" tumors. With a focus on antifibrotic therapies, specifically as combination strategies, this paper examines how these advancements might enhance the efficacy of treatments in both "hot" and "cold" tumors².

Cancer Immunotherapy: A Brief Overview

Initially developed for advanced metastatic cancer, immunotherapy has transitioned from a last-line option to a cornerstone in first- and second-line treatments for cancers like melanoma, lung, and bladder cancer. It is now frequently combined with targeted therapies and chemotherapies. By modulating adaptive immunity, these therapies block immunosuppressive signals or enhance immunostimulatory pathways. Key approaches include immune checkpoint inhibitors, adoptive cell therapies (e.g., CAR-T, TCR-T), cancer vaccines, monoclonal antibodies, cytokines, oncolytic viruses, and immune system modulators.

While there are many types of immunotherapies, checkpoint inhibitors and CAR-T therapies have received particular focus due to their unparalleled impact on cancer treatment and their significant clinical and market success. These approaches have achieved groundbreaking outcomes that distinguish them from other immunotherapy modalities, making them the leaders in transforming patient care.

Leading Approach: Checkpoint Inhibitors

Checkpoint inhibitors dominate the field, achieving notable efficacy across multiple cancers with U.S. sales surpassing $20 billion in 2023. These drugs counteract immune suppression in the tumor microenvironment by blocking interactions between checkpoint proteins (e.g., PD-1, PD-L1, CTLA-4) and their ligands, restoring T-cell activation and tumor targeting. Their mechanism of enhancing the immune system’s natural ability to detect and destroy cancer cells has proven effective across a broad range of cancers, including melanoma, lung, bladder, and head and neck cancers.

Currently, seven checkpoint inhibitors are FDA-approved:

• Anti-PD-1: Pembrolizumab, Nivolumab, Cemiplimab
• Anti-PD-L1: Atezolizumab, Avelumab, Durvalumab
• Anti-CTLA-4: Ipilimumab

The widespread applicability, established survival benefits, and durable responses of checkpoint inhibitors make them the backbone of many cancer immunotherapy regimens. They address immune suppression at a systemic level, enabling broad effectiveness across solid tumors and hematologic malignancies.

Adoptive Cell Therapy

CAR-T therapy represents a revolutionary advance in adoptive cell therapy, leveraging a patient’s own immune cells to target tumor-specific antigens with precision. This personalized approach has achieved curative outcomes in hematologic cancers, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), where traditional therapies often fail. Six FDA-approved CAR-T therapies, including Yescarta and Kymriah, have generated $3 billion in U.S. sales in 2023, underscoring their transformative impact.

Current CAR-T therapies engineer T cells to express chimeric antigen receptors (CARs) that recognize tumor-specific antigens, enabling them to target and eliminate cancer cells effectively. TCR-T therapies, a related approach, further advance this field by customizing T-cell receptors to target tumor antigens in solid tumors. In 2024, afamitresgene autoleucel became the first FDA-approved engineered TCR-T therapy for synovial sarcoma, marking a breakthrough for solid tumor treatment.

Emerging innovations like allogeneic “off-the-shelf” cell therapies aim to address the logistical challenges of autologous CAR-T approaches, offering scalable solutions to broaden patient access. Together, CAR-T and TCR-T therapies demonstrate the potential for precision immunotherapy to achieve dramatic outcomes and expand the scope of cancer treatment.

The field continues to evolve, with over 1,500 clinical trials globally exploring CAR-T, TCR-T, and checkpoint inhibitors. This innovation underscores the rapid pace of discovery, positioning these therapies as benchmarks for the next generation of cancer treatment.

Table 1. FDA approved immunotherapies, as above January 2025

The Tumor Microenvironment: Immunotherapy “no fly zone”

While checkpoint inhibitors and CAR-T therapies are at the forefront of the immunotherapy revolution, offering life-changing benefits and serving as a foundation for future advancements in the fight against cancer, there is promising research showing that antifibrotic combination treatments have the potential to improve the efficacy of both of these treatments, and others. This potential stems from the role of fibrosis and the tumor microenvironment (TME) in limiting immune responses to cancer.

The ability of immunotherapy to overcome the formidable barriers of the TME is a decisive factor in its success, with fibroblasts playing a critical, sometimes underestimated role. Fibroblasts, along with immune cells, tumor cells, and the extracellular matrix, shape the TME’s architecture and functionality. These cells contribute to the physical and biochemical landscape, influencing immune cell infiltration, response, and the tumor’s susceptibility to immune-based treatments. By modulating fibroblast activity within the TME, researchers hope to better manipulate its composition and ultimately enhance the effectiveness of immunotherapeutic strategies. It is interesting that these challenges were evident in the early development of CAR-T therapies, yet meaningful progress has been frustratingly slow over the past decade¹⁵.

Categorizing Tumors by Immune Phenotype

Immune cells, particularly CD8+ T cells and NK cells, are crucial in executing the immune response against tumors. However, tumors can manipulate the TME to exclude immune cells or suppress their function, evading immune detection and destruction. Tumors can be usefully categorized into three immune phenotypes based on their immune cell infiltration³: immune-inflamed (hot), immune-excluded (cold), & immune-deserted (cold).

Hot tumors, which have high levels of T-cell infiltration, are generally more responsive to immunotherapy and are marked by CD8, PD-L1, and IFN -γ, indicating active immune engagement. In contrast, immune-excluded or “cold” tumors feature immune cells confined to the stromal regions, unable to enter the tumor. These are associated with markers such as CXCL12, TGF-β, and VEGF, which contribute to physical and biochemical barriers to immune cell entry. For immune-deserted tumors, low MHC Class I expression, Wnt/β-catenin pathway activation, and low chemokine levels such as CCL4 hinder immune cell recruitment and recognition.

Additionally, VAR2’s recombinant malaria protein, has shown potential in targeting a specific chondroitin sulfate modification present on tumor cells, suggesting it could serve as a candidate marker, particularly for immune-excluded or immune-deserted (“cold”) phenotypes as well as an example of a possible new therapeutic target.

How Immune Exclusion Arises

Immune exclusion from the TME arises from multiple mechanisms that collectively hinder effective T cell infiltration and function. One key factor is the presence of mechanical barriers, such as stromal fibrosis and disordered vasculature. Dense fibrous tissue around tumors, often promoted by transforming growth factor-beta (TGF-β), physically obstructs T cell entry. Immune cell entry is often further restricted by abnormal blood vessel formation in tumor as a result of poor perfusion.

Additionally, a lack of chemotactic factors, such as essential chemokine gradients (e.g., CXCR-3 and CCR-5), limits T cell recruitment, often confining them to the tumor periphery. Immunosuppressive cytokines like TGF-β and IL-10, secreted by the tumor, create an unfavorable environment by inducing T cell exhaustion or apoptosis, thus reducing functional T cell availability. Moreover, immunosuppressive cells, such as regulatory T cells (Tregs), M2 macrophages and myeloid-derived suppressor cells (MDSCs), are prevalent in the TME, where they inhibit effector T cell activity, establishing a local immunosuppressive environment that suppresses anti-tumor responses.

Cancer-associated fibroblasts (CAFs) further contribute to immune exclusion by remodeling the ECM and secreting factors that repel T cells¹⁴. For example, CXCL12 from CAFs exerts a chemo-repulsive effect on CXCR4-expressing T cells, preventing them from reaching tumor cells¹⁵.

How Antifibrotic Therapies Can Reduce TME Barriers

Antifibrotic therapies represent a promising approach to dismantling the fibrous tissue surrounding solid tumors. These treatments target the excessive production and deposition of ECM components, particularly collagen, which contribute to the formation of a dense, protective barrier around cancer cells. By breaking down this fibrous shield, antifibrotic therapies aim to increase the accessibility of tumors to both the immune system and other cancer treatments, potentially enhancing their overall effectiveness³.

By reducing the physical and biochemical barriers within the TME, antifibrotic therapies can improve drug penetration, enhance immune cell infiltration, and potentially reverse the immunosuppressive nature of the TME. Current applications and ongoing trials have shown promising results in various cancer types. For instance, in pancreatic cancer, combining antifibrotic agents with chemotherapy has demonstrated improved drug delivery and efficacy¹⁴. Similarly, studies in liver cancer have shown that targeting fibrosis can enhance the effectiveness of immunotherapies, highlighting the potential of antifibrotic therapies as key players in revolutionizing solid tumor treatment strategies.

Additional Synergistic Effects of Combination Treatments

Furthermore, the combination of antifibrotic therapies with immunotherapies holds potential for synergistic effects. By softening the dense TME, antifibrotics may allow greater immune cell access and enhance the activation potential of immune checkpoint inhibitors or CAR-T cells. This combined approach represents an innovative pathway for addressing the immunosuppressive barriers in solid tumors, particularly in cancers with limited responses to current immunotherapies. As research continues, antifibrotics could redefine how challenging tumors are approached, providing an avenue for enhanced therapeutic outcomes in cancer treatment¹².

Recent Antifibrotics Cancer Research and Promising Clinical Trials

Recent studies have begun to explore the use of antifibrotic drugs to treat cancer in clinical settings, showing promising results in combination with other treatments. For example, a study published in Clinical Cancer Research in September 2024 highlighted that nintedanib combined with chemotherapy improved outcomes in patients with high fibrosis scores in breast cancer. This marked the first successful clinical application of targeting tumor fibrosis in oncology. Additionally, there was a significantly reduced risk of recurrence in patients with high fibrosis levels, further validating the potential of antifibrotic strategies in improving cancer treatment¹⁴.

The Phase II trial aimed to examine the effects of adding the antifibrotic agent nintedanib to paclitaxel in patients with early HER2-negative breast cancer, particularly focusing on its impact on tumor stiffness and relapse risk. Investigators assessed primary endpoints including changes in mechanical conditioning (MeCo) scores, relapse rates, and overall disease progression. Key findings indicated that patients with high MeCo scores—linked to increased tumor stiffness—experienced a significantly higher relapse risk in the paclitaxel-only group. However, in the experimental group receiving both nintedanib and paclitaxel, MeCo scores were reduced by 25% during the run-in phase, effectively lowering the relapse risk associated with fibrosis. Importantly, patients whose MeCo scores dropped to low levels after nintedanib treatment exhibited the best long-term outcomes, underscoring the therapeutic advantage of addressing tumor fibrosis. This study highlights how combining antifibrotic therapies like nintedanib with standard treatments or immunotherapies could improve patient outcomes, potentially by modifying the tumor microenvironment and enhancing immune system access to tumor cells. Other drugs, like pirfenidone and saracatinib, are being investigated for their antifibrotic properties and potential to enhance cancer treatment, particularly in colorectal cancer and pancreatic ductal adenocarcinoma (PDAC)¹⁴.

Complementary Mechanisms of Action

Despite the promising results of antifibrotic agents like nintedanib in combination with chemotherapy, antifibrotics have yet to be extensively tested alongside immunotherapy in clinical settings. The potential for synergy between antifibrotics and immunotherapy lies in their complementary mechanisms of action. Antifibrotics target and reduce tumor-associated fibrosis, effectively softening the TME and decreasing physical barriers that limit immune cell infiltration. By altering the TME in this way, antifibrotics could enable greater access for immune cells and enhance the efficacy of immunotherapeutic agents, which rely on immune cell activation and direct engagement with cancer cells. Combining antifibrotics with immunotherapies, such as checkpoint inhibitors or CAR-T cells, could thus improve patient outcomes by both modulating the TME and amplifying the immune response against tumors.

Table 2. A selection of antifibrotic drugs being investigated as cancer therapy.

The Cold Tumor Challenge

Certain cancers, like pancreatic, prostate, and ovarian cancers, are often described as “cold” tumors due to their low levels of immune cell infiltration. These cancers present significant challenges in immunotherapy because they often evade immune recognition or create immunosuppressive environments that hinder the immune response ¹³.

Prostate cancer has demonstrated modest responses to immunotherapy, primarily due to its immunosuppressive tumor microenvironment. In a study involving the immune checkpoint inhibitor pembrolizumab, only about 5% of patients with metastatic castration-resistant prostate cancer (mCRPC) showed a response, highlighting the challenge of achieving efficacy in cancers with immunosuppressive barriers ¹⁰.

Pancreatic cancer has also shown limited efficacy with immunotherapy, largely due to its dense stromal environment and low mutational burden. The KEYNOTE-158 study reported an overall response rate (ORR) of 34.3% across patients with various microsatellite instability-high (MSI-H) solid tumors, including endometrial and gastric cancers. However, the response rate in the subset of patients with pancreatic ductal adenocarcinoma (PDAC) was notably lower, at just 18.2%, demonstrating the difficulties in treating pancreatic cancer with immune-based approaches ¹¹.

Could Antifibrotics be the Key to Treating Cold Tumors?

To make cold tumors more responsive to immunotherapy, researchers are exploring strategies that modify the TME to improve cell access and activation. Current approaches include antifibrotic therapies to soften dense stroma, vascular normalization to enhance blood flow, and targeting immunosuppressive cells like Tregs and MDSCs. Additional methods involve inhibiting TGF-B activating the STING pathway, modulating chemokines to attract T cells, using oncolytic viruses to prime immune responses, and applying epigenetic modulators to boost tumor antigen expression.
Antifibrotic drugs like losartan, an angiotensin II receptor blocker, have shown promise in reducing fibrosis in pancreatic cancer models. By modulating TGF-β signaling and reducing ECM production, losartan has been observed to enhance immune cell infiltration and improve the effectiveness of chemotherapeutic agents, particularly in challenging tumors with high fibrotic content. Nintedanib, a multi-kinase inhibitor with antifibrotic properties, is also being studied in combination with chemotherapy for HER2-negative breast cancer. In these studies, nintedanib demonstrated the ability to reduce fibrosis and create a more permissive environment for immune cell activity, thereby potentially improving the effectiveness of immunotherapy.

Table 3. A selection of current approaches aimed at enhancing immune responsiveness in ‘cold’ tumors across various cancer types.

Conclusion: The Future of Immunotherapy and Antifibrotics in Cancer Treatment

Cancer immunotherapy continues to redefine oncological treatment, offering transformative options for patients with previously intractable diseases. While significant progress has been made, challenges persist, particularly in overcoming the dense stromal barriers and immunosuppressive environments of cold tumors. Advances in antifibrotic therapies, alongside emerging combination approaches with immune checkpoint inhibitors and CAR-T cells, highlight a promising pathway to enhance treatment efficacy across diverse cancer types. Moreover, the development of allogeneic cell therapies and novel strategies targeting the TME offer hope for more accessible, scalable, and effective interventions. As ongoing clinical trials and research efforts expand the boundaries of what is possible, the integration of these strategies may ultimately unlock the full potential of immunotherapy, ensuring its impact is felt by an even broader range of cancer patients.

 

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