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Cancer remains one of the most pressing challenges in modern medicine, but recent advancements are revolutionizing both therapeutic and diagnostic landscapes. This exploration of new frontiers in cancer therapy and diagnostics highlights a diverse array of innovative strategies that target the molecular mechanisms of tumorigenesis while enhancing early detection and personalized care. Cutting-edge therapies, such as small-molecule inhibitors and monoclonal antibodies, specifically target oncogene-driven pathways, offering selective toxicity over traditional chemotherapy. Immunotherapies, including immune checkpoint inhibitors, radioimmunotherapy, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapy, activate the immune system to combat malignancies, showing remarkable efficacy in oncogene-addicted cancers and hematological malignancies. Emerging approaches like cancer vaccines and oncolytic viruses further amplify immune responses, while liquid biopsy transforms diagnostics by analyzing circulating tumor markers for early detection, treatment monitoring, and resistance profiling. Artificial intelligence (AI) and machine learning amplify these advances, refining diagnosis through image analysis, predicting oncogenic mutations, and guiding personalized treatment plans. Together, these breakthroughs—including targeted therapies, immunotherapies, and technology-driven diagnostics—represent a major progress in oncology, though challenges like drug resistance, tumor heterogeneity, and accessibility persist. This summary highlights the promise and complexity of these new frontiers, paving the way for more effective, tailored cancer management.
Among the most promising novel therapeutic strategies designed to combat cancer are targeted therapy and immunotherapy, which leverage precision medicine that targets specific proteins and genetic changes driving tumor heterogeneity [1]. Unlike traditional chemotherapy, which nonselectively harms all cells, targeted therapy and immunotherapy focus on abnormal proteins or immune responses, minimizing toxicity to healthy cells [1][2]. These approaches encompass a range of techniques, including small-molecule inhibitors, monoclonal antibodies, immune checkpoint inhibitors, radioimmunotherapy, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, cancer vaccines, and oncolytic viruses [3][4][5].
Small-molecule inhibitors are broadly used in targeted therapy designed to slow or kill tumor cells by primarily targeting protein kinases, which are highly active pro-growth signaling initiators [6] (Figure 1). Their low molecular weight allows them to diffuse through cells and target intracellular drivers that regulate proliferation and apoptosis [2]. The list of various U.S. Food and Drug Administration (FDA)-approved small-molecule inhibitors for cancer treatment is shown in (Table 1). The predominant and widely accepted class of small-molecule inhibitors includes those targeting RTKs and VEGF receptors, such as Erlotinib, Sunitinib, and others, which exert antiangiogenic and antiproliferative effects [7]. Recent breakthroughs have shown promising applications of small-molecule inhibitors in treating oncogene-driven mutations [2]. Serval inhibitors for BRAF of the MAPK pathway, such as Vemurafenib and Dabrafenib, have shown effective results against melanomas. Moreover, these inhibitors are particularly potent in treating patients with Ras and BRAF V600E mutations when used in combination with general MAPK inhibitors like Trametinib [2][8]. Despite their promise, small-molecule inhibitors have limitations, as they lead to the development of drug resistance through mechanisms that may include their influence on tumor microenvironments and the potential reactivation of both MAPK and PI3K/AKT signaling pathways [8][9]. Additionally, resistance may arise from the changes occurring in the genes coding for target proteins, deviation in signaling pathways that activate different proteins with similar functions, or mutations in the genes coding for the proteins associated with the target molecule [10][11].
Monoclonal antibodies are immunoglobulins designed to bind specific antigens and represent the second most common form of targeted therapy [1][6]. Unlike small-molecule inhibitors, monoclonal antibodies are larger molecules that cannot enter cells. Instead, they work by targeting receptors on the surfaces of cancer cells, thereby blocking the molecules that signal proliferation or angiogenesis [2][12] (Figure 1). This approach is primarily used to target the antigens associated with oncogene signaling, thus inhibiting the pathways that promote cancer cell growth and survival [13]. The most common clinical applications of monoclonal antibodies are trastuzumab (targeting HER2), cetuximab (targeting EGFR), and pembrolizumab (targeting the PD-1/PD-L1 axis) [14][15][16]. Trastuzumab, for example, effectively disrupts oncogenic signaling by downregulating HER2, an RTK that is commonly overexpressed in HER2-positive breast cancer, thereby promoting its internalization and degradation [17][18]. Similarly, cetuximab and panitumumab bind to EGFR, preventing ligand binding and receptor dimerization, which inhibits oncogene signaling [19][20]. Moreover, the use of antibody therapy extends to tumor suppressors, as treatments with pembrolizumab or nivolumab have been shown to restore T-cell functionality against tumors, compensating for the LOF mutations in tumor suppressors[19][21].
Immunotherapy is a major treatment method and a promising therapeutic approach, especially in people with oncogene-addicted cancers—cancers that depend heavily on a single oncogene or pathway[22]. This treatment increases the ability of the immune system to recognize and eliminate cancer cells, mainly through immune checkpoint inhibitors that block pathways like PD-1, PD-L1, and CTLA-4, which tumors exploit to decrease immune responses [23]. Notably, pembrolizumab and nivolumab, previously discussed as monoclonal antibodies, overlap with this category, as they release the brakes on T cells and are very effective against oncogene-driven cancers that have mutations in genes like KRAS and EGFR [4][24]. Tumors with mutated KRAS are likely to respond better due to upregulated PD-L1 expression and immune cell infiltration, as opposed to EGFR and ALK-driven tumors, which typically have “cold” tumor microenvironments with fewer immune cells [22][25][5]. Immunotherapy may also improve outcomes for tumors with genomic instability, including mutations in tumor-suppressor genes such as TP53, STK11, and KEAP1[24][26]. Moreover, immunotherapy has also shown success when combined with chemotherapy and anti-angiogenesis agents like bevacizumab, which work synergistically to change the tumor microenvironment[25][27].
Radioimmunotherapy (RIT) is an extension of immunotherapy that combines targeted radiation with monoclonal antibodies to selectively target and destroy cancer cells[28]. This approach delivers a high dose of therapeutic or tracer radiation while minimizing exposure to normal cells[29]. Recent studies have focused on optimizing the combination of targeted radiation and immunotherapy, particularly in treatments that use alpha (radium-223 and actinium-225) and beta radionuclides (90y-ibritumomab tiuxetan), which have shown cytotoxic effects in treating leukemia, prostate cancer, and non-Hodgkin lymphoma [30][31]. Beyond its cytotoxic capabilities, RIT can influence oncogene and tumor-suppressor gene activity. For instance, a study by Guo et al. [32] identifies the correlation between p53 and RIT efficacy in tumors with wild-type TP53. The study found that, in response to RIT, the activity of p53 was upregulated, which led to increased apoptosis and better regulation of DNA damage in cancer cells. This suggests that RIT could benefit patients with functional tumor-suppressor pathways, serving as an alternative therapy in cases resistant to conventional treatments [32].
Figure 1. Mechanisms of action of small-molecule inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and radionuclides in cancer therapy. Small-molecule inhibitors target key receptors and kinases to disrupt signaling pathways and block tumor progression. Monoclonal antibodies recognize and bind specific antigens on the tumor cell surface, leading to immune-mediated destruction. Immune checkpoint inhibitors enhance T-cell activity by blocking inhibitory immune signals, restoring the immune system’s ability to recognize and eliminate tumor cells. Radioimmunotherapy combines monoclonal antibodies with radionuclides to selectively deliver cytotoxic radiation to tumor cells, increasing treatment precision while minimizing damage to normal tissues. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/k49h851.
Antibody–drug conjugates (ADCs) are a class of targeted cancer therapy that connects monoclonal antibodies with a potent cytotoxic drug (payload) through a chemical linker [33]. The monoclonal antibody offers a highly specific targeting capability, thus binding to a target antigen on the cancer cell’s surface. The presence of a chemical linker ensures that the payload, which has a highly potent cytotoxic effect, is released only inside the cancer cell, therefore minimizing the damage to healthy tissues[34]. The first FDA-approved ADC was the anti-CD33-targeted agent gemtuzumab ozogamicin in 2000, to treat patients with acute myeloid leukemia[35]. Since then, there have been eleven FDA-approved ADCs (Table 2) for targeting various tumor antigens, such as CD19, CD22, CD30, CD33, and CD79b in blood cancers (myeloma, lymphoma, and leukemia), and HER2, tissue factor, folate factor alpha, Nectin-4, and Trop-2 in solid cancers (NSCLC, breast cancer, gastric cancer, and ovarian cancer, among others[36], and many more are in advanced stages of clinical trials.
ADC Generic Name | Target Antigen | Cytotoxic Payload | FDA Approval |
---|---|---|---|
Loncastuximab tesirine | CD19 | SG3199, alkylating agent (DNA targeting) |
2021 (Diffuse Large B-Cell Lymphoma—DLBCL) |
Inotuzumab ozogamicin | CD22 | Calicheamicin (cytotoxic antibiotic) |
2017 (B-cell Acute Lymphoblastic Leukemia—ALL) |
Brentuximab vedotin | CD30 | Monomethyl auristatin E (microtubule targeting) |
2011, 2015, 2018 (Hodgkin lymphoma—HL; 2011, 2017, 2018 (Anaplastic Large Cell Lymphoma—ALCL); 2018 (Peripheral T-Cell Lymphoma—PTCL) |
Gemtuzumab ozogamicin | CD33 | Calicheamicin (cytotoxic antibiotic) |
2017 (Acute Myeloid Leukemia—AML) |
Polatuzumab vedotin | CD79b | Monomethyl auristatin E (microtubule targeting) |
2019, 2023 (DLBCL) |
Trastuzumab emtansine | HER2 | DM1 (microtubule targeting) |
2013, 2019 (HER2+ Breast Cancer) |
Trastuzumab deruxtecan | HER2 | Topoisomerase I inhibitor (DNA targeting) |
2019, 2022 (HER2+ Breast Cancer); 2021 (Gastric Adenocarcinoma—GAC or Gastroesophageal Junction—GEJ Adenocarcinoma); 2022 (NSCLC) |
Tisotumab vedotin | Tissue Factor | Monomethyl auristatin E (microtubule targeting) |
2021 (Cervical Cancer) |
Mirvetuximab soravtansine–gynx | Folate Receptor Alpha |
DM4 (microtubule targeting) |
2022 (Ovarian Cancer, Fallopian Tube Cancer, and Peritoneal Cancer) |
Enfortumab vedotin | Nectin-4 | Monomethyl auristatin E (microtubule targeting) |
2019, 2023 (Urothelial Cancer) |
Sacituzumab govitecan | Trop-2 | SN-38 topoisomerase-1 inhibitor (DNA targeting) |
2020 (Triple-Negative Breast Cancer—TNBC); 2021 (Urothelial Cancer); 2023 (HER2- Breast Cancer, HR+ Breast Cancer) |
Chimeric antigen receptor (CAR) T-cell therapy is a novel cancer therapy that uses patients’ own T cells to fight cancer[37]. Usually, the T cells do not present receptors specific to the cancer cells’ antigens, which prevents them from attaching to the antigens and destroying the cancer cells. In CAR T-cell therapy, T cells are extracted from the patient’s blood and undergo genetic modification, which introduces a gene that encodes a cancer-specific antigen receptor on their cellular membrane, enabling them to recognize and attach to the cancer cell [38]. Then, CAR T cells are infused back into the patients, where they circulate and attack cancer cells. This therapy has shown a significantly greater promise in targeting and combating circulating blood cancers like leukemia, lymphomas, and myelomas compared to solid tumors, mostly because of the solid tumors’ inaccessibility due to their complex microenvironment [39]. So far, there are six FDA-approved CAR T-cell products for treating hematological malignancies (Table 3), and many more are in active clinical trials[40].
CAR T-Cell Product Generic Name |
Target Antigen | FDA Approval |
---|---|---|
Tisagenlecleucel | CD19 | 2017 (ALL); 2018 (DLBCL); 2022 (Follicular lymphoma—FL) |
Axicabtagene ciloleucel | CD19 | 2017, 2022 (DLBCL, PMBCL); 2021 (FL) |
Brexucabtagene autoleucel | CD19 | 2020 (Mantle Cell Lymphoma—MCL); 2021 (ALL) |
Lisocabtagene maraleucel | CD19 | 2021, 2022, 2024 (DLBCL, PMBCL) |
Idecabtagene vicleucel | BCMA | 2021, 2024 (Multiple Myeloma—MM) |
Ciltacabtagene autoleucel | BCMA | 2022, 2023 (MM) |
Despite the significant advancements and successes of targeted therapies and immune therapy, these approaches have many persistent limitations that hinder their success. Cancer cells frequently adapt, developing resistance that reduces the effectiveness of treatments like monoclonal antibodies, small-molecule inhibitors, ADCs, CAR T-cell products, and immune checkpoint inhibitors over time[41]. The resistance often stems from genetic mutations, altered signaling pathways, or changes in the tumor microenvironment, such as variable vasculature and immune suppression [42]. Additionally, these therapies can cause a spectrum of secondary effects that impact patients’ quality of life, including but not limited to skin toxicity, high blood pressure, and heart damage to severe autoimmune reactions like cytokine release syndrome (CRS), neurotoxicity, swelling, nausea, vomiting, diarrhea or constipation, allergic reactions, and hair loss [43]. Moreover, the complexity of these treatments, especially ADCs and CAR T-cell products, demands specialized manufacturing and delivery, increasing the costs and limiting their widespread availability and accessibility [44][45]. Addressing these challenges and limitations of targeted cancer therapies is crucial for improving therapeutic outcomes and treatment strategies to overcome these challenges.
Cancer vaccines can be clinically used therapeutically or preventively and are delivered in four forms: cell-based, viral/bacterial-based, peptide-based, and nucleic acid-based vaccines (Figure 2) [46][47]. These vaccines use tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) to elicit an immune response in patients that would provoke both cellular and humoral immune responses to eradicate tumors and prevent tumorigenesis [47][48]. Cell-based vaccines are prepared using whole tumor cells or cell fragments, which can be injected directly or loaded on DCs with adjuvants to enhance immunogenicity [47][49]. Viral/bacterial-based vaccines are naturally immunogenic, and their genetic material can be engineered to express tumor antigens [47]. Peptide-based vaccines contain biosynthetic peptides that represent known tumor antigens to stimulate the immune system to attack particular tumor sites [47]. Lastly, nucleic acid-based vaccines deliver genetic material that encodes tumor antigens, thus inducing MHC I-mediated CD8+ T-cell responses, making it one of the more promising approaches [47][50].
Figure 2. Types of cancer vaccines. There are four types of cancer vaccines: cell-based, viral/bacterial-based, peptide-based, and nucleic acid-based vaccines. Cell-based vaccines are prepared using whole tumor cells or tumor cell fragments. which can be injected directly or loaded onto dendritic cells along with adjuvants to enhance their immunogenicity and stimulate a stronger anti-tumor immune response. Viral/bacterial-based vaccines are designed using recombinant viral or bacterial vectors to deliver genetic material encoding cancer-specific proteins or antigens. These vectors infect host cells, enabling the expression of the target antigens and stimulating an immune response against cancer cells. Peptide-based vaccines use short biosynthetic peptides that mimic specific tumor epitopes of tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) to stimulate the immune system to recognize and attack cancer cells at specific tumor sites where the target antigens are expressed. Nucleic acid-based vaccines deliver genetic material (RNA or DNA) that encodes tumor-specific antigens. The RNA or DNA is typically encapsulated in carriers to protect it from degradation and facilitate efficient delivery into the host cells. Once inside, the genetic material is expressed, producing the target antigens, which are then presented to the immune system. This stimulates T and B cells to recognize and attack cancer cells that express these antigens. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/c04n703.
Therapeutic cancer vaccines have shown great success in clinical trials [46]. Several therapeutic vaccines that have been approved by the FDA are already in use against various cancers (Table 4) [46]. Sipuleucel-T was the first FDA-approved therapeutic cell-based vaccine for metastatic prostate cancer [51]. The prolonged disease course of advanced prostate cancer creates a window where the body can generate an immune response against the cancer cells [52]. Another example is the bacillus Calmette–Guerin (BCG) vaccine, which is a bacterial-based vaccine used to treat early-stage bladder cancer [46]. BCG uses inactivated tuberculosis bacteria, which is administered through a catheter to stimulate an immune response, causing apoptosis, necrocytosis, and oxidative stress [53][54].
While therapeutic vaccines target existing tumors, prophylactic/preventive cancer vaccines aim to reduce the initial risk of cancer development, primarily protecting against virus-induced cancers [46]. One of the two currently approved and common prophylactic cancer vaccines is the Human Papillomavirus (HPV) vaccine (Table 6), which utilizes a virus-like particle of the non-oncogenic and non-infectious papillomavirus capsid protein L1 to build an immune response that would prevent HPV from inserting itself into the host’s genome and cause nuclear aberrations [55][56]. The other prophylactic vaccine in use is the Hepatitis B vaccine, which is a common liver infection that leads to liver cirrhosis and hepatocellular carcinoma (HCC) (Table 4) [57]. A study by Cao et al. [58] showed that the Hepatitis B vaccine offers 72% protection against liver cancer post-infection.
ADC – Antibody–Drug Conjugate
AI – Artificial Intelligence
AKT – Protein Kinase B
ALK – Anaplastic Lymphoma Kinase
AML – Acute Myeloid Leukemia
BCG – Bacillus Calmette–Guérin
BRAF – v-Raf Murine Sarcoma Viral Oncogene Homolog B
CAD – Computer-Aided Diagnoses
CAR – Chimeric Antigen Receptor
CNN – Convolutional Neural Network
CRS – Cytokine Release Syndrome
CTCs – Circulating Tumor Cells
ctDNA – Circulating Tumor DNA
CTLA-4 – Cytotoxic T-Lymphocyte-Associated Protein 4
DAMP – Damage-Associated Molecular Patterns
DC – Dendritic Cell
EGFR – Epidermal Growth Factor Receptor
ELCAP – Early Lung Cancer Action Program
ERBB2 – Erb-B2 Receptor Tyrosine Kinase 2 (synonym for HER2)
EVs – Extracellular Vesicles
FASTK – Fas-Activated Serine/Threonine Kinase
FAT1 – FAT Atypical Cadherin 1
FDA – U.S. Food and Drug Administration
FLT3 – Fms-Like Tyrosine Kinase 3
H2AW – H2A.W Histone
HCC – Hepatocellular Carcinoma
HER2 – Human Epidermal Growth Factor Receptor 2
HPV – Human Papillomavirus
IGFALS – Insulin-Like Growth Factor Binding Protein Acid Labile Subunit
KEAP1 – Kelch-Like ECH-Associated Protein 1
KRAS – Kirsten Rat Sarcoma Viral Oncogene Homolog
LIDC – Lung Image Database Consortium
LOF – Loss of Function
MAP2K1 – Mitogen-Activated Protein Kinase Kinase 1 (MEK1)
MAPK – Mitogen-Activated Protein Kinase
MET – Mesenchymal-Epithelial Transition Factor
miRNA – MicroRNAs
ML – Machine Learning
MM – Multiple Myeloma
MRD – Minimal Residual Disease
NGS – Next-Generation Sequencing
NRAS – Neuroblastoma RAS Viral Oncogene Homolog
NSCLC – Non-Small Cell Lung Cancer
PCR – Polymerase Chain Reaction
PD-1 – Programmed Cell Death Protein 1
PD-L1 – Programmed Death-Ligand 1
PI3K – Phosphoinositide 3-Kinase
POLR3K – RNA Polymerase III Subunit K
RIT – Radioimmunotherapy
ROS – Reactive Oxygen Species
ROS1 – ROS Proto-Oncogene 1, Receptor Tyrosine Kinase
RTK – Receptor Tyrosine Kinases
SETBP1 – SET Binding Protein 1
STK11 – Serine/Threonine Kinase 11
TAA – Tumor-Associated Antigen
TME – Tumor Microenvironment
TP53 – Tumor Protein p53
TSA – Tumor-Specific Antigen
T-VEC – Talimogene Laherparepvec
VEGF – Vascular Endothelial Growth Factor
WES – Whole Exome Sequencing