Over the past decade, significant advancements have led to new therapies that improve survival rates and offer alternatives to traditional treatments like chemotherapy and radiation. From immune checkpoint inhibitors to CAR-T cell therapies, immuno-oncology continues to shape the future of cancer care.

Ongoing research focuses on enhancing treatment efficacy through combination therapies, leveraging biomarkers for personalized approaches, and overcoming challenges like tumor heterogeneity and acquired treatment resistance, ultimately aiming to improve clinical outcomes and advance precision cancer medicine.

This article provides an overview of recent developments in the field, highlighting key innovations, ongoing research, and the challenges that remain. By understanding these advancements, researchers and clinicians can better navigate the evolving landscape of cancer immunotherapy and its role in improving patient outcomes.

Fundamentals of cancer immunology

A long-standing notion that gained clinical momentum more than a century ago is the immune system's ability to influence tumor growth. As a result, a comprehensive understanding of how elements of both innate and adaptive immunity identify and react to tumors has been developed, and this knowledge is being used to build cancer immunotherapies.

Tumor immunology

Tumor immunology explores the complex interplay between cancer cells and the immune system, highlighting the influence of immune surveillance and immunoediting on tumor development and progression.

Recent breakthroughs in understanding the immune landscape of cancer, including the types, densities, and distribution of immune cells within the tumor microenvironment (TME), have greatly improved how we classify and predict cancer outcomes. This new understanding is helping to shape the development of exciting immunotherapies, like checkpoint inhibitors and CAR T cell therapies. These treatments work by leveraging the immune system to specifically target and destroy cancer cells, making way for more personalized and effective cancer treatment options.

Cancer immunology studies help:

• Explore interactions between immune cells and tumors.
• Differentiate immune-rich (hot) and immune-poor (cold) tumors.
• Uncover mechanisms of immune evasion.
• Analyze the tumor microenvironment (TME) to enhance cancer therapies.

Tumor microenvironment (TME)

Tumor cells induce significant molecular, cellular and physical changes within their host tissues. The TME is a complex and continuously evolving ecosystem. Its composition varies between tumor types but typically features immune cells, supportive stromal cells, and blood vessels embedded in a modified network of extracellular matrix. From the nascent stages of cancer development, tumor cells closely modulate their surrounding environment to ensure survival. They migrate to nearby tissues and organs, promoting angiogenesis, to enhance their oxygen and nutrient supply.

Within the TME, immune cells can either fight cancer or, in some cases, actually help it grow by weakening the body's natural defenses. Supportive stromal cells, including those that form blood vessels and specialized fibroblasts, release substances that encourage angiogenesis, tissue invasion, and the breakdown of the surrounding structure, all of which aid the tumor’s progression.

Additionally, non-cellular components like the extracellular matrix provide physical support and act as storage for growth factors, while exosomes help cancer cells communicate with and influence surrounding cells to promote inflammation and tumor growth. Recent research on the TME reveals new strategies to disrupt supportive interactions, presenting promising opportunities to enhance existing cancer treatments and develop therapies that effectively prevent tumor growth and spread.

Hot vs. cold tumors

Hot and cold tumors refer to the level of immune activity within a tumor, which influences how well the tumor responds to immunotherapy.

Hot tumors exhibit abundant immune cell infiltration, particularly activated T cells, and an inflammatory microenvironment that enhances responsiveness to immunotherapies like checkpoint inhibitors. Conversely, cold tumors lack significant immune cell presence and display an immunosuppressive microenvironment, making them less susceptible to immunotherapies and often requiring combination strategies to stimulate immune engagement.

Distinguishing between hot and cold tumors by analyzing their molecular profiles and microenvironments is essential for tailoring therapeutic approaches, improving clinical outcomes, and advancing personalized cancer treatment.

Immune surveillance and evasion

The immune system can recognize and destroy cancer cells through a physiological process called immune surveillance. Recent studies have highlighted the role of tumor suppressor genes in evading immune surveillance. The p53 tumor suppressor, encoded by the TP53 gene, is a master regulatory transcription factor.

It controls multiple core programs in cells, including cell-cycle arrest, apoptosis, senescence, metabolism, and several immune signaling pathways, including pathogen sensing, cytokine production, and inflammation. Cancer cells with TP53 mutations rely on multiple strategies to evade the immune system. While downregulation of MHC Class I and II molecules, loss of TRAIL receptors, and upregulation of PD-L1 expression aids in evading T cell mediated killing, downregulation of NK-activating ligands and suppression of the cGAS-STING pathway evades NK cell attack.

On the other hand, cancer cells carrying p53 mutations significantly alter the phenotype and function of macrophages and neutrophils within the tumor microenvironment, often leading to an immunosuppressive state that promotes tumor growth and metastasis by influencing their recruitment, activation, and cytokine production. In addition, they tend to enhance inflammation in response to inflammatory cytokines and chemokines, generating a positive feedback loop, further promoting tumor progression.

These findings reveal new immune evasion mechanisms, suggesting that targeting tumor suppressor gene-related pathways could enhance the effectiveness of existing immunotherapies such as T cell receptor (TCR)-T cells or chimeric antigen receptor (CAR)-T cells and pave the way for novel cancer treatment strategies.

Immune cell types and their role in cancer immunity

The immune system fights cancer using innate cells like natural killer (NK) cells, macrophages, and adaptive T and B cells. Cytokines help control these cells, while immune checkpoint inhibitors targeting programmed cell death protein PD-1 and cytotoxic T-lymphocyte antigen (CTLA)-4 boost the immune response.

Innate immune cells

Innate immune cells play a vital role in the body’s defense against cancer, complementing the adaptive immune system. Cells like macrophages, dendritic cells, NK cells, and myeloid-derived suppressor cells (MDSCs) can directly attack tumor cells or help activate other immune cells to do so. For instance, NK cells are capable of identifying and destroying cancer cells without prior sensitization, while dendritic cells present tumor antigens to T cells, kickstarting a targeted immune response.

However, tumors often create an environment that suppresses these innate immune functions, allowing cancer to grow and evade detection. To counter this, scientists are developing therapies that enhance the activity of innate immune cells, such as CAR-NK cell therapies and drugs that reprogram macrophages to become tumor-fighting allies. By leveraging and boosting the innate immune system, these innovative treatments aim to improve cancer control and increase the number of patients who benefit from immunotherapy.

Adaptive immune cells

Adaptive immune cells, including T cells and B cells, play a critical role in recognizing and responding to cancer. CD8+ cytotoxic T cells directly target and kill tumor cells by recognizing tumor-associated antigens (TAAs) via MHC, while CD4+ helper T cells support the immune response by activating other immune cells, like cytotoxic T cells. B cells produce antibodies to target tumor cells, facilitating immune responses such as antibody-dependent cellular cytotoxicity.

However, tumors can exploit immune checkpoints, such as PD-1/PD-L1 and CTLA-4, to suppress T cell activity and evade immune detection. Regulatory T cells (Tregs) and other immune suppressors within the tumor microenvironment can further dampen immune responses, allowing tumors to progress.

Despite these immune evasion strategies, adaptive immunity has the potential to eliminate tumors, especially through immunotherapies that enhance immune cell function. Checkpoint inhibitors, CAR T cell therapy, and cancer vaccines are designed to boost or restore immune responses against tumors. However, tumors can also adapt by altering antigen expression, suppressing immune activation, or promoting immune exhaustion. To address these challenges, combinations of CAR-T cell therapies with checkpoint inhibitors are being investigated for various cancers.

Immune checkpoints

Immune checkpoints serve an important physiological role in the immune system, designed to ensure that immune responses do not become excessively aggressive and damage the body’s healthy cells. The use of immune checkpoint inhibitors as immunotherapeutic drugs was a groundbreaking cancer treatment, and they help the immune system recognize and fight tumor cells more effectively. These therapies target specific proteins, such as PD-1, CTLA-4, LAG3, TIM3, TIGIT, and BTLA, which normally act as brakes to keep the immune response in check.

By blocking the immune checkpoints with the inhibitors, the brakes are released, allowing T cells and other immune cells to attack cancer cells with greater intensity. For example, drugs like anti-PD-1 and anti-CTLA-4 antibodies have shown success in treating various cancers by enhancing the body's natural ability to combat tumors.

However, not all patients respond to these treatments, especially those with cancers that have fewer mutations, and some may experience side effects like autoimmune reactions. Ongoing research aims to better understand the mechanism of these checkpoints and to develop new inhibitors, improving the effectiveness and safety of cancer immunotherapy.

Role of cytokines and chemokines in cancer

Cytokines and chemokines play a central role in modulating the immune response in cancer by influencing the activation and function of immune cells. Tumor cells often exploit the immune response to promote an immunosuppressive environment, with cytokines like IL-10, TGF-β, and IL-6 contributing to immune tolerance and resistance.

These cytokines can upregulate immune checkpoint molecules, such as PD-L1 on tumor cells, leading to T cell exhaustion and inhibition of effective anti-tumor immunity. Chemokines, such as CCL2, that regulate immune cell trafficking, can also support the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), further promoting immune suppression.

Together, cytokines and chemokines contribute to immune evasion by enhancing checkpoint signaling, leading to tumor progression and resistance to conventional therapies. While the therapeutic benefit of cytokine inhibitors in combination with immune checkpoint inhibitors (ICI) is being adopted to restore anti-tumor immunity, cytokine replacements are being leveraged to improve the efficacy of ICIs.

Immunotherapy approaches in cancer

Immunotherapy is most commonly associated with cancer treatment, which involves influencing the host immune system to improve outcomes. Various immunotherapies, such as immune checkpoint inhibitors, CAR T cell therapy, and monoclonal antibodies, work by enhancing the body's natural defenses.

Our Cancer immunotherapy: immune checkpoint poster provides an overview of the cancer immunity cycle and how immunotherapy can be a powerful tool in the fight against cancer.

Immune checkpoint inhibitors (ICIs)

Immune checkpoint inhibitors (ICIs) work by blocking inhibitory signals within the immune system, thereby enhancing the body's ability to recognize and attack tumor cells. These inhibitors target immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4, which are commonly exploited by cancer cells to evade immune surveillance. By disrupting these checkpoint pathways, ICIs restore the function of T cells, allowing them to mount a more effective immune response against tumors. This approach has demonstrated significant clinical success, particularly in solid tumors.

The US Food and Drug Administration (FDA) has approved three classes of monoclonal antibody ICIs for the treatment of various cancers: PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, and Avelumab), and the CTLA-4 inhibitor Ipilimumab. Results from a clinical trial in cisplatin-ineligible patients with metastatic urothelial carcinoma, and treatment with Pembrolizumab resulted in a satisfactory durable response rate (DRR).

Another trial demonstrated a significant improvement in overall response rate (ORR) in head and neck squamous cell carcinoma patients. Clinical trials of Cemiplimab in patients with cutaneous squamous cell carcinoma revealed improved overall survival (OS) and progression free survival (PFS) as compared to EGFR inhibitors and chemotherapy.

Despite their effectiveness, resistance to ICIs remains a major challenge, prompting ongoing research to better understand their mechanisms and improve patient outcomes. While antibodies that target immune inhibitory receptors like CTLA-4, PD-1, and PD-L1 have been the most commonly used, numerous antibodies and small molecules targeting other immune checkpoint proteins, including B7H3, CD39, CD73, the adenosine A2A receptor, and CD47, are currently undergoing clinical development.

Moreover, recent research has uncovered several new immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), and V-domain Ig suppressor of T cell activation (VISTA).

Learn more about cancer immunotherapy and the PD-1/PD-L1 pathway, including its role in cancer progression and how it is utilized in treatment to enhance immune response.

Monoclonal antibodies and bispecific antibodies

Monoclonal antibodies (mAbs) have become a cornerstone of targeted anticancer therapy by specifically binding to tumor-associated antigens, thereby enhancing the immune system’s ability to suppress and eliminate cancer cells. Building on the success of IgG mAbs, diverse therapeutic antibody formats have been developed, including antibody fragments, bispecific antibodies (BsAbs), and derivatives such as antibody-drug conjugates (ADCs) and immuno cytokines, each designed to improve efficacy and reduce off-target effects.

The miniaturization of antibodies into smaller fragments like fragment-antigen binding (Fab) and single-chain Fv fragments (scFv) enhances tumor penetration, while multifunctionalization through bispecific and multispecific formats allows simultaneous targeting of multiple antigens or engagement of various immune effector cells, addressing the complexity of the TME.

ADCs exemplify this innovation by linking potent cytotoxic agents to mAbs, ensuring precise delivery of chemotherapy directly to cancer cells, thereby minimizing systemic toxicity and improving therapeutic outcomes. Immunocytokines, which fuse antibodies with cytokines, enable localized immune activation within the tumor and further amplify the anti-tumor response without eliciting a widespread inflammatory response.

Clinical advancements have demonstrated the effectiveness of these novel antibody formats in various cancers, with numerous FDA-approved therapies and ongoing clinical trials highlighting their potential. For example, several bispecific antibodies (BsAbs) have received approval, including those targeting CD19 using the bispecific T cell engager (BiTE) platform for acute lymphoblastic leukemia and those targeting clotting factors FIXa and FX through the asymmetric re-engineering technology (ART-Ig) platform for hemophilia treatment. Other BsAbs are currently in clinical trials.

As biotechnology continues to evolve, the design of sophisticated antibody derivatives promises to enhance the precision and potency of cancer immunotherapies.

CAR T cell therapy

CAR T cell therapy has transformed cancer treatment by engineering T cells to specifically recognize and destroy cancer cells, resulting in highly effective and long-lasting clinical responses. These engineered CARs enable T cells to bind directly to tumor antigens without the need for MHC presentation, leading to robust activation and powerful anti-tumor activity. The groundbreaking success of anti-CD19 CAR-T cells in treating B cell malignancies earned FDA approval in 2017, highlighting the therapy's potential.

However, CAR T cell therapy faces significant challenges, including severe toxicities, limited effectiveness against solid tumors, antigen escape, and difficulties with T cell persistence and tumor infiltration. To overcome these limitations, researchers are developing combination therapies and innovative CAR engineering techniques aimed at enhancing efficacy, preventing resistance, and reducing side effects.

Ongoing advancements focus on optimizing CAR designs and strategies to improve trafficking and persistence, ultimately expanding the reach and safety of CAR T cell therapy for a broader range of cancers.

Cancer vaccines

Cancer vaccines represent a promising advancement in immunotherapy for solid tumors, aiming to stimulate the body’s immune system to recognize and eliminate cancer cells. These vaccines deliver tumor antigens in various forms, including whole cells, peptides, and nucleic acids, to activate both humoral and cellular immune responses.

The best cancer vaccines are crafted to counteract the immunosuppressive TME, promoting strong and lasting anti-tumor immunity. Cancer vaccine development typically revolves around four main platforms:

• Cell-based vaccines are prepared using whole tumor cells or dendritic cells to mount broader immune responses.
• Virus-based vaccines employ viral vectors to deliver tumor antigens and stimulate immune responses.
• Peptide-based vaccines are made of specific tumor antigen epitopes that require adjuvants to enhance their immunogenicity.
• Nucleic acid-based vaccines, such as DNA and mRNA vaccines, encode tumor antigens for endogenous production and presentation.

Recent clinical research has shown encouraging results, particularly with personalized neoantigen vaccines that tailor the immune response to individual tumor mutations.

Ongoing innovations aim to enhance vaccine efficacy by optimizing antigen selection, improving delivery platforms, and combining cancer vaccines with other immunotherapies like immune checkpoint inhibitors. These efforts are important for advancing personalized cancer treatments and achieving effective and durable clinical outcomes.

Oncolytic viruses (OVs) and adoptive cell therapies (ACTs)

OVs and ACTs have independently emerged as powerful strategies in cancer immunotherapy, each utilizing unique mechanisms to target and eliminate tumor cells. OVs are engineered to selectively infect and lyse cancer cells, triggering immunogenic cell death that releases tumor antigens and stimulates the immune system. This process not only directly reduces tumor burden but also modifies the TME to become more conducive to immune cell activity.

ACTs, including therapies like CAR-T and NK cell treatments, involve the engineering or expansion of immune cells to specifically recognize and attack cancer cells with high precision. However, the effectiveness of ACTs in solid tumors is often limited by the immunosuppressive nature of the TME, which inhibits immune cell infiltration and function.

To overcome these barriers, OVs are combined with ACTs by using OVs to prime the TME, thereby enhancing the recruitment and activation of adoptively transferred cells. This synergy can lead to more robust and sustained anti-tumor responses, particularly in challenging solid tumor environments. Despite the promising potential, challenges such as optimizing OV replication, mitigating immune suppression, and preventing adverse immune reactions must be addressed.

Ongoing research focuses on engineering OVs to express immune-stimulatory molecules, enhancing ACT cell trafficking through genetic modifications, and targeting immunosuppressive cells within the TME. The complementary strengths of OVs and ACTs are being actively explored in clinical and preclinical studies to help patients with solid tumors achieve more effective and long-lasting results.

Key areas of focus in immuno-oncology research

The key to successful personalized immunotherapy begins with identifying the tumor's molecular signature. Biomarkers have emerged as powerful tools in both diagnosing cancer and guiding treatment decisions, especially in precision medicine. While identification of genetic mutations lays the foundation of personalized immunotherapy, predictive biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI) that assess the extent of genetic mutations and replication errors in tumors, respectively, are essential in immuno-oncology research to guide personalized immunotherapy strategies.

Biomarkers and immune cell markers

Genetic biomarkers are specific mutations in tumor DNA that drive cancer development, such as those in EGFR, BRAF, or HER2, which aid in accurate cancer classification and diagnosis. Genetic testing is also crucial for selecting patients for targeted therapies, as certain mutations make tumors more responsive to specific drugs. For instance, EGFR mutations in non-small cell lung cancer can be treated with EGFR inhibitors, and BRCA1/2 mutations in breast or ovarian cancer may respond to PARP inhibitors.

Moreover, genetic testing helps predict cancer risk by identifying inherited mutations linked to higher susceptibility. BRCA1 and BRCA2 mutations increase the risk of breast, ovarian, and other cancers, while MLH1 and MSH2 mutations are associated with Lynch syndrome and colorectal cancer. Early genetic screening enables preventive actions, such as more frequent screenings or risk-reducing surgeries, to lower cancer risk and improve outcomes.

An imbalance in circulating cytokines and dysregulated cytokines signaling signature of peripheral immune cells have emerged as predictive biomarkers of cancer treatment. For example, in renal cell carcinoma, increased levels of IL-6 correlate with cancer metastasis, while high IL-6 and IL-17 measurements predict cancer recurrence following radical treatment. Moreover, elevated levels of IL-6, TNF-α, and IL-10 have been associated with poor prognosis in various cancers, while elevated plasma VEGF levels in various cancer patients are negatively correlated with tumor prognosis.

Other biomarkers include genomic indicators like TMB and HLA-I diversity, immune-related gene expression profiles, the presence and functionality of tumor-infiltrating lymphocytes (TILs), and microbiome composition, each reflecting different facets of the anti-tumor immune response.

TMB and MSI

TMB, defined as the total number of somatic non-synonymous mutations within a cancer genome, serves as a predictive biomarker for patient response to immune checkpoint inhibitors, leading to the FDA’s disease-agnostic approval of pembrolizumab for TMB-high tumors. Despite its clinical utility, standardizing TMB measurement, determining optimal mutation thresholds across diverse cancer types, and ensuring accurate assessments through large sequencing panels and sufficient tumor purity remain challenging.

Emerging improvements focus on refining the TMB framework by incorporating clonal and HLA-corrected TMB, assessing tumor neoantigen load and mutational signatures, and integrating TMB with other biomarkers like PD-L1 expression, MSI, and immune gene expression profiles.

MSI, also known as short tandem repeats (STRs) or simple sequence repeats (SSRs), refers to variations in the number of repeated nucleotide sequences caused primarily by DNA replication errors and deficiencies in the mismatch repair (MMR) system, which lead to increased mutation rates in tumor cells. MSI is classified into high (MSI-H), low (MSI-L), and stable (MSS) categories, with MSI-H being particularly relevant in cancers such as colorectal, gastric, and endometrial, where it serves as an important biomarker for prognosis and predicting responses to immunotherapies like PD-1 inhibitors.

Despite its clinical significance, challenges such as standardizing MSI assessment protocols, determining optimal mutation thresholds across diverse cancer types, and integrating MSI with other biomarkers like TMB persist, prompting refining detection techniques and enhancing the predictive power of MSI through comprehensive genomic and immunological profiling.

Innovations and advancements in immuno-oncology research

Advances in preclinical models, biomarkers, trial designs, high-throughput technologies, metabolic studies, and artificial intelligence (AI)-driven tools enhance the precision, personalization, and efficacy of immuno-oncology therapies.

Advances in immuno-oncology assays and techniques

• Advances in immuno-oncology assays and techniques have significantly enhanced the precision and efficacy of cancer immunotherapies by developing sophisticated preclinical models, such as humanized mouse systems and patient-derived organoids, which can accurately mimic the human TME and immune interactions.
• The integration and refinement of biomarkers, including TMB, MSI, and PD-L1 expression, have improved patient stratification and predictive accuracy for immunotherapy responses, facilitating more personalized treatment approaches.
• Innovative clinical trial designs like adaptive platforms and master protocols have streamlined the evaluation of numerous immuno-oncology agents and combinations, accelerating the transition from preclinical research to clinical application.
• The advancements in high-throughput technologies, such as next-generation sequencing and liquid biopsies, have enabled comprehensive genomic and immunological profiling, allowing for real-time monitoring of treatment efficacy and the identification of resistance mechanisms.

Metabolic immuno-oncology

• Metabolic immuno-oncology investigates the complex interactions between cancer cell metabolism and the immune system's capacity to combat tumor growth.
• Metabolic immuno-oncology studies explore the malignant cells that continuously activate specific metabolic pathways to sustain their proliferation and evade immune detection.
• The TME helps cancer cells adjust to low oxygen and nutrients while also creating conditions that weaken immune cells. Cancer cells and stromal cells engage in a dynamic metabolic dialogue, mutually influencing each other’s metabolic states to either promote tumor progression or facilitate regression.
• Understanding the mechanisms driving these metabolic alterations and the subsequent crosstalk between tumor and immune cells remains an important area of research, holding significant implications for the development of targeted therapies.

Emerging trends in cancer immunotherapy

Emerging trends in cancer immunotherapy include combination treatments, harnessing the application of microbiome to boost immune responses, and utilizing nanomedicine for precise drug delivery. These advancements enhance efficacy and reduce side effects.

Combination therapies in immuno-oncology

Combination therapies in immuno-oncology integrate multiple treatment modalities to enhance the immune system’s ability to target and eliminate cancer cells more effectively than single-agent therapies.

• By combining immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1/PD-L1 antibodies as a core treatment strategy, multiple pathways that tumors use to evade immune detection can be targeted.
• Incorporating targeted therapies like tyrosine kinase inhibitors (TKIs) or epigenetic modulators alongside checkpoint blockers can disrupt tumor growth signals and modify the TME to be more conducive to immune cell activity.
• Combining immunotherapies with conventional treatments like chemotherapy and radiotherapy can induce immunogenic cell death, releasing tumor antigens that further stimulate an anti-tumor immune response.
• Bispecific antibodies and bifunctional agents offer dual targeting capabilities, engaging both immune cells and tumor-specific antigens to enhance cytotoxicity and reduce immune evasion.
• OVs and nanoparticles serve as innovative delivery systems, directly lysing tumor cells while simultaneously activating immune responses and improving the delivery of immunotherapeutic agents.
• Adoptive T cell therapies, such as CAR T cells, when combined with checkpoint inhibitors, can overcome T cell exhaustion and enhance the persistence and efficacy of engineered immune cells within the TME.
• Metabolic modulators and ion channel blockers are emerging as novel combination partners, aiming to reprogram the metabolic landscape of the tumor and support sustained immune function.
• Personalized combination strategies, guided by biomarkers and comprehensive profiling of the tumor and immune landscape, are important for maximizing therapeutic outcomes and minimizing adverse effects.

Despite the significant promise, challenges such as managing immune-related adverse events, overcoming patient-to-patient variability, and ensuring the optimal timing and sequencing of combination agents remain vital in ongoing research. Future advancements are expected to leverage AI and multi-omics approaches to design more effective and tailored combination therapies, ultimately expanding the range of cancers that can be successfully treated with immuno-oncology strategies.

The role of the microbiome in immuno-oncology

The microbiome plays a pivotal role in immuno-oncology by modulating the host immune system's ability to recognize and combat cancer cells. Specifically, the tumor microbiome, comprising diverse microorganisms within the TME, directly influences immune response regulation and tumor progression through mechanisms such as cytokine production and immune cell activation.

Certain bacterial species, like Faecalibacterium and Akkermansia muciniphila, have been associated with enhanced efficacy of immune checkpoint inhibitors, demonstrating that microbial composition can significantly impact immunotherapy outcomes.

Additionally, microbial metabolites, including short-chain fatty acids, can alter immune cell function and improve the responsiveness of tumors to immunotherapeutic agents by modulating pathways like PD-1/PD-L1. However, the high interindividual variability in microbiome composition presents challenges for standardizing microbiome-based therapies, necessitating personalized approaches to optimize treatment efficacy.

Opportunities arise in leveraging probiotics, fecal microbiota transplantation, and microbiome-derived biomarkers to tailor immunotherapies, enhance treatment responses, and predict patient outcomes. Furthermore, integrating multi-omic analyses can deepen our understanding of the intricate interactions between the tumor microbiome and the immune system, facilitating the identification of novel therapeutic targets.

Future research directions emphasize the need for large-scale studies to validate microbiome influences on immunotherapy and the development of precise, targeted interventions to manipulate the tumor microbiome safely and effectively.

Nanomedicine and targeted drug delivery systems

Nanomedicine enables precise and efficient targeted drug delivery to tumor sites, thereby enhancing therapeutic efficacy while minimizing systemic toxicity. Utilizing advanced nanocarriers such as liposomes, polymeric nanoparticles, and gold nanostructures, these systems exploit the enhanced permeability and retention effect to accumulate selectively within the TME.

Stimuli-responsive nanoparticles can intelligently release their payload in response to specific tumor-associated triggers like acidic pH or elevated reactive oxygen species, ensuring that immunotherapeutic agents are activated precisely where needed. This targeted approach not only improves the bioavailability and stability of drugs but also overcomes biological barriers, facilitating deeper tumor penetration and sustained immune activation.

Additionally, nanomedicine can co-deliver multiple therapeutic agents, such as combining immune checkpoint inhibitors with cytokines or vaccines, to orchestrate a synergistic anti-tumor immune response.

Despite these advancements, challenges like making treatments safe for the body, preventing immune rejection, and targeting all parts of tumors still exist, requiring continued research and innovation. Ultimately, the integration of nanotechnology with immunotherapy holds immense potential to personalize and optimize cancer treatment, offering hope for more effective and less adverse therapeutic outcomes.

Clinical applications and challenges

Immuno-oncology trials with PD-1/PD-L1 inhibitors and pediatric CAR T cells show promise but face challenges like limited durable responses, resistance, trial design complexities, disparities, and data integration, necessitating advanced strategies and biomarkers.

Clinical trials

Clinical trials in immuno-oncology have been transformed by agents targeting the PD-1/PD-L1 axis, providing long-term benefits and potential cures for cancers previously deemed incurable. However, only a minority of patients achieve durable responses with these immune checkpoint inhibitors alone, leading to the development of combination therapies that pair immune checkpoint inhibitors with chemotherapies, targeted treatments, and other immunotherapies to enhance effectiveness.

Despite promising results in improving survival for cancers like melanoma and lung cancer, many combination trials advance to phase III without sufficient predictive biomarkers or optimized designs, resulting in challenges in demonstrating clear benefits. To improve trial outcomes, organizations like the Society for Immunotherapy of Cancer have created frameworks and checklists to guide the design and evaluation of phase III studies, aiming to maximize patient benefits and streamline the development of effective immuno-oncology treatments.

Addressing challenges in immuno-oncology research

Immuno-oncology research grapples with complex clinical trial designs that require advanced computational models and adaptive strategies to optimize dosing, timing, and combination therapies while effectively managing immune-related adverse events through predictive algorithms and sophisticated imaging techniques.

Significant cancer disparities persist due to unequal access to molecular profiling and clinical trials, necessitating AI-driven solutions to enhance personalized treatments and reduce financial toxicity for diverse patient populations. Data integration and sharing further complicate progress, as the heterogeneity of multimodal datasets challenges biomarker discovery and the effective application of AI, highlighting the need for standardized protocols and collaborative platforms to fully understand the tumor-immune microenvironment.

Addressing the shortage of trained bioinformatics professionals and fostering team science across multidisciplinary domains are essential to leverage high-dimensional data, advance tumor antigen discovery, and implement spatial biology insights, ultimately driving the development of more personalized and equitable immunotherapy treatments.

Personalized immuno-oncology

Personalized immuno-oncology utilizes genomic profiling, AI-driven vaccines, and liquid biopsies to tailor cancer treatments and monitoring, enhancing efficacy and early detection while addressing challenges like tumor heterogeneity and biomarker sensitivity.

Genomic profiling and pharmacogenomics

Genomic Profiling refers to the process of analyzing the genetic makeup of an individual or a tumor to identify specific genetic mutations, alterations, or variations. This information is vital for understanding disease mechanisms, such as how cancer develops, and for tailoring personalized treatment strategies. Genomic profiling helps clinicians identify targeted therapies, predict disease progression, and choose the most effective interventions based on the genetic characteristics of the disease.

Pharmacogenomics, on the other hand, is the study of how an individual’s genetic makeup affects their response to drugs. By understanding genetic variations, pharmacogenomics enables the customization of drug treatments to enhance efficacy and minimize adverse effects. It can guide the selection of medications, the determination of optimal dosages, and the avoidance of harmful drug interactions based on genetic factors, improving overall treatment outcomes.

Together, genomic profiling and pharmacogenomics represent key aspects of personalized medicine, where treatments are tailored not only to the disease but also to the patient’s unique genetic profile. This approach holds great promise for improving the precision and effectiveness of medical treatments, particularly in cancer care and chronic diseases.

Personalized cancer vaccines

Personalized cancer vaccines are engineered to target unique tumor-specific neoantigens derived from an individual’s specific genetic mutations, thereby enhancing the immune system's ability to recognize and eliminate cancer cells with high precision. The incorporation of AI into vaccine development significantly accelerates the identification and selection of these neoantigens, optimizes vaccine formulations, and predicts patient-specific immune responses, thereby increasing both the efficacy and safety of the vaccines.

Clinical studies have demonstrated the potential of personalized vaccines in eliciting robust immune responses and improving clinical outcomes in patients with advanced cancers like non-small cell lung cancer and glioblastoma. However, challenges such as tumor heterogeneity, accurate neoantigen prediction, and ensuring equitable access across diverse populations remain, necessitating ongoing interdisciplinary collaboration and the addressing of ethical and regulatory considerations to fully realize the promise of AI-driven personalized cancer immunotherapies.

Liquid biopsies and non-invasive diagnostics

Liquid biopsies enable the non-invasive extraction and analysis of circulating biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and cell-free DNA (cfDNA) from blood and other bodily fluids, thereby facilitating early cancer detection, real-time monitoring of treatment responses, and the identification of minimal residual disease.

Leveraging advanced sequencing technologies and biomarker-based cell capture methods, liquid biopsies can comprehensively profile tumor heterogeneity and dynamically track tumor evolution, offering significant advantages over traditional invasive tissue biopsies by allowing for repeated sampling and immediate clinical decision-making.

Beyond oncology, liquid biopsies hold immense potential in diverse medical specialties, including cardiology, where they can detect myocardial infarction biomarkers and infectious diseases through the identification of pathogen-derived DNA, and neurology by monitoring neurodegenerative disease markers, so broadening their applicability across various disease states.

However, the widespread adoption of liquid biopsies is hindered by challenges such as limited sensitivity and specificity due to low concentrations of tumor-derived components, the need for standardized protocols and quality control measures, high costs associated with advanced technologies, and regulatory hurdles, all of which must be addressed to fully realize their potential as a mainstream diagnostic and monitoring tool in clinical practice.

Future directions in immuno-oncology research

Future scope in immuno-oncology research lies in overcoming immune resistance by targeting tumor mechanisms and suppressive cells, enhancing treatment efficacy through combination therapies and CAR-T improvements, and utilizing mRNA vaccines for precise, scalable, and safe cancer targeting.

Overcoming immune resistance

• Overcoming immune resistance in cancer immunotherapy requires a multifaceted approach that targets both intrinsic and extrinsic tumor mechanisms.
• Enhancing antigen presentation by restoring or upregulating HLA molecules and neoantigen load can improve T cell recognition and eliminate immune evasion strategies employed by cancer cells.
• Targeting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages within the TME can alleviate inhibitory signals and bolster anti-tumor immune responses.
• Combining immune checkpoint inhibitors with targeted therapies, utilizing advanced genomic profiling for personalized treatment plans, and employing computational tools to identify and mitigate resistance pathways are essential strategies to effectively overcome immune resistance and enhance the efficacy of immunotherapeutic interventions.

Expanding treatment efficacy

• Expanding the efficacy of immunotherapy in cancer treatment involves overcoming the immunosuppressive TME that limits the effectiveness of immune checkpoint inhibitors beyond cancers like melanoma and non-small cell lung cancer.
• Researchers are actively exploring combinatory immunotherapies, such as pairing checkpoint inhibitors with cytotoxic treatments, cancer vaccines, and monoclonal antibodies targeting additional co-inhibitory and co-stimulatory receptors, to enhance anti-tumor responses and counteract T cell exhaustion.
• Strategies to improve the homing, extravasation, and survival of CAR T cells within tumors are being developed, alongside personalized approaches targeting multiple neoantigens to boost specificity and reduce immune-related adverse events.
• Important to these advancements is the identification and utilization of precise biomarkers, which enable the tailoring of combination therapies to individual patients, thereby maximizing therapeutic efficacy.

The potential of mRNA vaccines in immuno-oncology

• mRNA vaccines can be meticulously designed to encode specific tumor-associated and tumor-specific antigens, including unique neoantigens derived from an individual’s genetic mutations, thereby enhancing the immune system's ability to recognize and eliminate cancer cells while minimizing damage to healthy tissues.
• Advances in mRNA vaccine design and delivery technologies enable the rapid development of personalized cancer vaccines tailored to an individual's tumor profile, facilitating timely treatment interventions and accommodating the dynamic nature of tumor evolution and heterogeneity.
• Utilizing lipid nanoparticles (LNPs) as delivery vehicles significantly improves the stability and cellular uptake of mRNA vaccines, protects the mRNA from degradation, ensures efficient delivery to target cells, and promotes robust and sustained immune activation.
• mRNA vaccines offer a strong safety profile as they do not integrate into the host genome, reducing the risk of long-term adverse effects.
• The relatively low-cost and scalable manufacturing processes make mRNA vaccines an economically viable option for widespread clinical application.

FAQs

How does next-generation sequencing (NGS) enhance immuno-oncology research?

Next-generation sequencing (NGS) enhances immuno-oncology research by enabling precise identification of tumor-specific neoantigens and assessing tumor mutational burden, which is important for predicting patient responses to immune checkpoint inhibitors and other immunotherapies. Additionally, NGS facilitates the development of personalized immunotherapeutic strategies, such as tailored cancer vaccines and engineered T cell therapies, by providing comprehensive genomic profiles for advanced treatments.

What is the significance of cancer immunoediting in immuno-oncology?

Cancer immunoediting is fundamental to immuno-oncology as it delineates the dynamic interactions between the immune system and tumor cells, encompassing the phases of elimination, equilibrium, and escape, which collectively influence tumor immunogenicity and progression. By understanding these mechanisms, researchers and clinicians can develop targeted immunotherapies that not only enhance the immune system's ability to eradicate cancer cells but also prevent or overcome tumor-mediated immune evasion, thereby improving treatment efficacy and patient outcomes.

How does the multiomics approach improve our understanding of tumor biology?

The multiomics approach enhances our understanding of tumor biology by integrating diverse molecular data—including genomics, transcriptomics, proteomics, and metabolomics—to reveal the complex interactions and heterogeneity within tumors. Additionally, spatial multiomics provides an important context by mapping the spatial distribution and interactions of various cell types and molecular markers in the TME, thereby identifying precise therapeutic targets and improving the prediction of treatment responses for personalized cancer therapy.