Advanced Immunotherapy and Cell Therapy: Approaches for Solid Tumours
Ahmad Fitri Idris *
*Correspondence to: Ahmad Fitri Idris, UK.
Copyright.
© 2025 Ahmad Fitri Idris This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 15 May 2025
Published: 31 May 2025
Introduction
The field of cancer therapeutics is being revolutionized by immunotherapy and cell-based therapies, offering new hope for patients facing solid tumours that were previously difficult to treat. Traditional treatments like chemotherapy and radiation often have limited effectiveness and cause significant toxicity, highlighting the critical need for innovative strategies that can use the immune system to selectively target and eliminate cancer cells. 1 Immunotherapy harnesses the immune system's ability to recognize and destroy abnormal cells, providing the potential for long-lasting remissions and better patient outcomes.1 The success of immune checkpoint inhibitors and advancements in creating genetically modified immune cells have shifted the focus from treating the tumour itself to boosting the host's immune system to recognize and eliminate cancer cells. Decades of research in T-Cell biology and tumour immunology have paved the way for cancer immunotherapy to move from a promising concept to a standard treatment for many types of tumors. Recent progress in cancer immunotherapy, including checkpoint blockade, adoptive cell therapy, and oncolytic virotherapy, has shown long-lasting anti-tumour responses in patients with advanced-stage malignancies, even after conventional treatments have failed.1
Immune Checkpoint Inhibitors: Unleashing the Power of T Cells
A key element of modern cancer immunotherapy is the modulation of immune checkpoints, which are regulatory pathways that fine-tune immune responses to prevent excessive inflammation and autoimmunity. Cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 are two well-studied immune checkpoints that play a critical role in suppressing T cell activity within the tumour microenvironment. The development of antibodies targeting CTLA-4 and PD-1 has transformed cancer treatment, leading to lasting responses in some patients with various solid tumors.1
Immune checkpoint inhibitors work by blocking these inhibitory signals, thereby unleashing the cytotoxic potential of T cells and allowing them to effectively target and destroy cancer cells. The interaction between PD-1 and PD-L1, which can be expressed on tumour cells, leads to immune suppression by preventing the activation of T cells in the tumour. While controversial for many years, cancer immunotherapy reached a turning point in 2014 with the approval of antibodies specifically blocking PD-1 for melanoma. The remarkable clinical efficacy of immune checkpoint inhibitors has solidified their role as a mainstay of cancer therapy, particularly for malignancies such as melanoma, non-small cell lung cancer, and renal cell carcinoma.
Overcoming Resistance to Immune Checkpoint Inhibitors
Despite their success, the clinical efficacy of immune checkpoint inhibitors is limited to a subset of patients, highlighting the need for strategies to overcome resistance mechanisms and enhance therapeutic responses. Resistance to PD-L1/PD-1 blockade immunotherapy remains a significant clinical challenge. Several mechanisms contribute to this resistance, including:
Strategies to overcome resistance to immune checkpoint inhibitors include combining them with other therapies, such as chemotherapy, radiation therapy, and other immunotherapeutic agents. Additionally, researchers are exploring novel approaches to enhance T cell infiltration, block immunosuppressive factors, and restore antigen presentation.
Adoptive Cell Therapy: Engineering Immune Cells to Fight Cancer
Adoptive cell therapy is another promising approach in cancer immunotherapy, involving the ex vivo manipulation and expansion of immune cells to enhance their anti-tumour activity before infusing them back into the patient.1 This approach aims to overcome the limitations of the natural immune response by providing a large number of highly active immune cells that can effectively target and destroy cancer cells.
CAR-T Cell Therapy: A Paradigm Shift in Cancer Treatment
One of the most successful forms of adoptive cell therapy is CAR-T cell therapy, which involves genetically modifying T cells to express a chimeric antigen receptor that specifically recognizes a tumour-associated antigen. T cells are collected from a patient's blood, genetically modified to express the CAR, and then expanded in large numbers before being infused back into the patient. The CAR allows the T cells to recognize and bind to cancer cells expressing the target antigen, leading to their activation and destruction. CAR-T cell therapy has shown remarkable efficacy in treating haematological malignancies, such as leukaemia and lymphoma. However, its application to solid tumors has been more challenging.2 3
Challenges and Strategies for CAR-T Cell Therapy in Solid Tumors
Despite the success of CAR-T cell therapy in haematological malignancies, several challenges limit its efficacy in solid tumors:
Researchers are actively working to overcome these challenges by developing novel CAR designs, engineering CAR-T cells to resist immunosuppression, and combining CAR-T cell therapy with other treatments, such as oncolytic viruses and immune checkpoint inhibitors.1
Other Forms of Adoptive Cell Therapy
Besides CAR-T cell therapy, other forms of adoptive cell therapy are being explored for the treatment of solid tumors, including:
Oncolytic Virotherapy: Harnessing Viruses to Destroy Cancer Cells
Oncolytic viruses are genetically engineered viruses that selectively infect and kill cancer cells while sparing normal cells. These viruses can also stimulate an anti-tumour immune response, further contributing to their therapeutic efficacy. Oncolytic virotherapy has shown promise in treating various solid tumors, either as a monotherapy or in combination with other treatments.
Intra-tumoral Immunotherapy: A Localized Approach
Intra-tumoral immunotherapy involves the direct injection of immunotherapeutic agents into the tumour. This approach allows for high concentrations of the drug to be delivered directly to the tumour while minimizing systemic toxicity. Intra-tumoral immunotherapy can be used to deliver various agents, including immune checkpoint inhibitors, oncolytic viruses, and cytokines.
Targeting the Tumor Microenvironment
As highlighted in the provided document, the tumour microenvironment plays a crucial role in influencing the effectiveness of cancer immunotherapy. Factors such as tissue microarchitecture, stiffness, solid stress, and interstitial fluid pressure contribute to immunosuppression and therapy resistance. Additionally, tumour cells compete with tumour-infiltrating lymphocytes for nutrients, impairing T cell function. Cancer-associated fibroblasts also contribute to immune suppression by inducing the deletion of tumour-reactive T cells.
Strategies to target the TME include:
Future research and conclusion
Immunotherapy and cell therapy have emerged as revolutionary approaches in cancer treatment, offering durable responses and improved outcomes for patients with solid tumors. 1 While significant progress has been made, challenges remain in optimizing these therapies for broader clinical application. Overcoming the immunosuppressive tumour microenvironment, identifying suitable target antigens, and enhancing T cell infiltration and persistence are crucial for maximizing the potential of cancer immunotherapy and cell therapy. Future research should focus on personalized approaches, combination strategies, and biomarker development to tailor immunotherapeutic strategies to individual patient and tumour characteristics, ultimately leading to more effective and durable treatments for a wide range of solid malignancies.
The complex interplay between cancer cells and the surrounding tumour microenvironment (TME) presents a significant hurdle to effective cancer treatment.1 2 Therapeutic resistance often arises from the adaptive mechanisms within the TME rather than solely from changes within the tumour cells themselves.2 Treating cancer effectively necessitates a comprehensive understanding of the tumour ecosystem, considering not only the tumour cells but also the diverse range of interacting host cells and environmental factors.1 By modulating the tumour microenvironment and targeting immunosuppressive pathways, researchers aim to create a more favourable environment for immune-mediated tumour destruction.2 3 4
Myeloid cells, including tumour-associated macrophages, tumour-associated neutrophils, and myeloid-derived suppressor cells, profoundly influence the nature of the TME, serving as both positive and negative mediators of tumour growth.1 These cells contribute to immune evasion, angiogenesis, and matrix remodelling, thus modulating the tumour's interaction with the immune system.1 The functional state of intra-tumoral myeloid cells varies, with some promoting tumoricidal activity through direct cytotoxicity and T cell stimulation, while others suppress anti-tumour immunity by producing immunosuppressive cytokines and recruiting regulatory T cells. The tumour microenvironment is a complex system composed of cancer cells, immune cells, mesenchymal cells, and their secreted mediators, creating a supportive niche for tumour proliferation and metastasis.1 Cytokines, lipid mediators, and extracellular matrix components within the TME contribute to angiogenesis, tumour cell survival, and inactivation of T cell anti-tumour responses.1 Tumor-associated macrophages, which can constitute a significant portion of the tumour mass, play a role in inflammation, hindering T cells and natural killer cells from attacking the tumour.1 The tumour microenvironment is a complex ecosystem that significantly influences tumour growth, invasion, metastasis, and treatment resistance.2 3 It consists of cellular components like immune cells, fibroblasts, endothelial cells, and the extracellular matrix.2 3 4 5
The microenvironment plays a major role in cancer phenotypes, including proliferation, invasion, metastasis, and drug resistance.2 3 4 The bidirectional interactions between tumour cells and the TME facilitate cancer progression and treatment resistance. Tumor cells can modify their surroundings by releasing factors that alter the microenvironment, influencing non-tumoral cells like endothelial cells, fibroblasts, and immune cells.2 The tumour microenvironment plays a major role in cancer phenotypes, including proliferation, invasion, metastasis, and drug resistance. Recent findings highlight the TME's contribution not only to tumorigenesis but also to maintaining cancer stemness and treatment resistance.2 3 By modulating the TME through targeting extracellular matrix components, immune checkpoint inhibitors, or angiogenesis inhibitors, researchers aim to overcome resistance mechanisms and improve treatment outcomes.
Furthermore, tumour cells can adapt to changing environmental conditions by utilizing a wide range of nutrients.2 The availability of nutrients and oxygen within the TME significantly influences tumour cell metabolism and immune responses.3 4 Cancer cells predominantly rely on aerobic glycolysis for energy production, even in the presence of oxygen.2 Alterations in nutrient metabolism within the TME can impact the activity of immune cells and influence the development of immunosuppressive mechanisms.6 Targeting metabolic pathways or modulating nutrient availability within the TME represents a promising strategy for enhancing the efficacy of cancer immunotherapies. The intricate relationship between cancer cells and the tumour microenvironment is increasingly recognized as a critical factor influencing cancer progression and treatment outcomes.40 41 42 43
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