Hallmarks of cancer—Four parametric dimensions

The "Hallmarks of Cancer" is a seminal conceptual framework created by Douglas Hanahan and Robert Weinberg to organize the daunting complexity of cancer into a logical set of principles. The series began in 2000 with a perspective positing six core functional capabilities that normal cells acquire as they become tumors.

As research evolved, the framework was updated in 2011 to include eight hallmarks and introduced the concept of "enabling characteristics" like genome instability. A ninth hallmark, unlocking phenotypic plasticity, was added in 2022. The most recent review ¹ in 2025 consolidates these decades of discovery into four parametric dimensions: the nine core hallmarks, five enabling characteristics, the specialized cells of the tumor microenvironment, and the systemic interactions between the tumor and the entire body.

1. Conceptual Evolution: From Six to Nine Hallmarks

The "Hallmarks of Cancer" framework, originally proposed by Douglas Hanahan and Robert Weinberg, serves as the definitive heuristic for organizing the immense genetic and phenotypic diversity of neoplastic disease. Rather than viewing cancer as a chaotic accumulation of random mutations, this framework identifies a logical series of acquired functional capabilities that allow "outlaw organs" to overcome biological barriers through multistep tumorigenesis and neo-Darwinian adaptation.

The framework has undergone rigorous chronological refinement to mirror our deepening molecular understanding:

• 2000: The original perspective established the foundational six hallmarks: sustaining proliferative signaling, inactivating growth suppressors, resisting programmed cell death, establishing replicative immortality, inducing vasculature, and activating invasion and metastasis.
• 2011: The model expanded to include two emerging hallmarks: deregulating cellular metabolism and evading immune destruction, alongside the introduction of "enabling characteristics."
• 2022/2025: A ninth hallmark, unlocking phenotypic plasticity, was codified to address the non-genetic transitions cancer cells utilize to navigate selective pressures.

To synthesize these developments, the 2025 Hanahan framework organizes the biology of cancer into Four Conceptual Dimensions:

1. Functional Capabilities: The nine core hallmarks of cancer.
2. Enabling Phenotypic Characteristics: Traits that facilitate the acquisition of those hallmarks.
3. Hallmark-Conveying Cells of the TME: The heterotypic "accessories to the crime" recruited and reprogrammed within the microenvironment.
4. Systemic Interactions: The complex interplay between the tumor and the host’s macroenvironment, including aging and obesity.

2. Dimension 1: The Nine Hallmarks—Acquired Functional Capabilities

The hallmark capabilities represent the essential operating system of the cancer cell. These functions are distinctive in their mechanistic execution and are necessary—to varying degrees—for progression across most human malignancies.

Summary of Hallmark Capabilities

Hallmark	Primary Biological Function	Key Associated Gene/Protein
Sustaining Proliferative Signaling	Chronic stimulation of the cell division cycle and oncogenic drivers.	KRAS, MYC, PIK3CA
Inactivating Growth Suppressors	Circumvention of gatekeeper programs and contact inhibition.	TP53, RB, APC
Resisting Programmed Cell Death	Avoiding apoptosis, ferroptosis, and necroptosis signaling.	BCL-2, BAX, MCL-1
Replicative Immortality	Disabling the telomeric "mitotic clock" to allow infinite division.	TERT (Telomerase), ATRX (ALT)
Inducing or Accessing Vasculature	Accessing nutrients via angiogenesis or invasive vascular co-option.	VEGFA, ANGPT2
Deregulating Cellular Metabolism	Reprogramming energetics through metabolic hybridity and symbiosis.	MYC, HIF-1α (Regulators)
Unlocking Phenotypic Plasticity	Escaping terminal differentiation or switching cell identities.	SOX2, SNAIL, TWIST
Evading Immune Destruction	Avoiding attack by T cells via exhaustion and immunosuppression.	PD-L1, CTLA-4, FOXP3
Activating Invasion and Metastasis	Executing the metastatic cascade and colonizing distant niches.	TP53, WGD (Markers)

Technical Analysis of Mechanisms

• Sustaining Proliferative Signaling: Most cancers are anchored by mutations in "driver" oncogenes. KRAS remains a dominant player, mutated in ~30% of human tumors, while MYC acts as a grand orchestrator, amplified or rearranged in 40% of cases to regulate thousands of genes.
• Inactivating Growth Suppressors: Cancers must abrogate the "oncogenic competence" of gatekeepers like TP53 (mutated in ~40% of cases) and RB. Beyond intrinsic loss, tumors circumvent paracrine "contact inhibition" and engage in cell competition for limited nutrients.
• Resisting Programmed Cell Death: While BCL-2 family members govern the intrinsic apoptotic pathway, modern oncology recognizes resistance to broader cell death programs, including ferroptosis (iron-dependent) and necroptosis. Paradoxically, apoptotic cells can release signals that stimulate hallmark-enabling qualities in neighboring cells.
• Establishing Replicative Immortality: Most cancers upregulate telomerase (TERT), often via promoter mutations. Mesenchymal and neuroepithelial tumors frequently employ Alternative Lengthening of Telomeres (ALT), a recombination-based mechanism.
• Inducing or Accessing Vasculature: Tumors induce a "leaky," chaotic neovasculature via VEGF/ANGPT2 signaling but also exhibit invasive vascular co-option, where cells migrate along existing vessels in normal tissue.
• Deregulating Cellular Metabolism: Cancer cells act as "metabolic hybrids," utilizing both aerobic glycolysis and oxidative phosphorylation. They exhibit metabolic symbiosis, where carboxylic acid metabolism and metabolic signaling (e.g., lactate uptake) fuel distinct subpopulations within the TME.
• Unlocking Phenotypic Plasticity: This involves three distinct modes of intra-lineage plasticity: (1) de-differentiation back to progenitor states, (2) blocked differentiation of transformed cells, and (3) shuttling between "cancer stem cell" (CSC) states. It also includes trans-lineage plasticity, such as the epithelial-mesenchymal transition (EMT), allowing for hybrid cell states.
• Evading Immune Destruction: Beyond T cell exhaustion, tumors systemically impair T cell development in lymphoid organs and recruit regulatory cells to create a barrier of "T cell paralysis."
• Activating Invasion and Metastasis: This cascade involves transition from primary invasion to dormancy and eventually colonization. While master "metastasis genes" remain elusive, Whole Genome Doubling (WGD) and Chromosomal Instability (CIN) are frequent drivers of this transition.

3. Dimension 2: The Five Enabling Phenotypic Characteristics

Enabling characteristics are not functional capabilities per se, but aberrant traits that facilitate the acquisition of hallmark functions.

• Loss of Genomic Integrity: This refers to the loss of DNA repair efficiency and telomere dysfunction, leading to CIN. Manifestations include aneuploidy, whole-genome doubling, and the generation of extrachromosomal DNA (ecDNA) or "shattered" chromosomes (chromothripsis).
• Non-Mutational Epigenetic Reprogramming: This separable characteristic involves three layers of control: (1) chromosomal domain accessibility, (2) transcription factor (TF) availability, and (3) post-transcriptional modifications of mRNA and proteins. This allows for phenotypic evolution without altering the primary DNA sequence.
• Tumor-Promoting Inflammation: Described as "wounds that fail to heal," tumors corrupt restorative mechanisms. Pathways such as cGAS-STING, TLR, and NF-κB can be co-opted to recruit innate immune cells that provide paracrine growth signals while suppressing adaptive immunity.
• Innervation: In the emerging field of "cancer neuroscience," peri- and intra-tumoral nerves release neurotransmitters that signal directly to cancer cells. High-impact findings from the 2025 Hanahan synthesis include mitochondrial transfer from nerves to cancer cells to support metastasis and the establishment of pseudo-tripartite synapses where cancer cells mimic astrocytes to colonize the brain.
• Polymorphic Microbiomes: Microbial dysbiosis in the gut, lung, or skin can modulate immune evasion and promote genomic instability via the secretion of mutagenic molecules. Fecal transplants have demonstrated that shifting the microbiome can restore sensitivity to immunotherapies.

4. Dimension 3: The Cellular Ecosystem—Hallmark-Conveying Cells of the TME

The TME is a heterotypic ecosystem where normal cells are reprogrammed as "accessories to the crime" to support tumor progression.

1. Cancer Stem Cells (CSCs): These cells represent a continuum of "cancer stemness," residing in protective niches and driving adaptive resistance and tumor seeding.
2. Endothelial Cells and Pericytes: Beyond structural support, these cells express ligands that induce T cell death and facilitate cancer cell intravasation. They are also involved in the formation of tertiary lymphoid structures (TLS).
3. Cancer-Associated Fibroblasts (CAFs): CAFs remodel the ECM and engage in metabolic symbiosis. They are categorized into myofibroblastic (myCAF) and inflammatory (iCAF) states, with some states potentially being tumor-suppressive.
4. TAMs and TANs: Tumor-associated macrophages and neutrophils exist on a spectrum from tumor-antagonizing (M1-like) to tumor-promoting (M2-like). They are often referred to as myeloid-derived suppressor cells (MDSCs) when in their immature, immunosuppressive states.
5. Regulatory Immune Cells: Tregs and Bregs are recruited to pacify the adaptive response. The FOXP3 transcription factor programs Tregs to suppress the effector functions of cytotoxic CD8 T cells.
6. Senescent Cells: Despite losing proliferative potential, senescent cells develop a Senescence-Associated Secretory Program (SASP). This SASP can paradoxically stimulate the growth of neighboring non-senescent cancer cells and promote a tumor-friendly environment.

5. Dimension 4: Cancer as a Systemic Disease—Key Interactions

Cancer interacts with the host "macroenvironment," which serves to modify hallmark acquisition and expression.

• Aging: Aged tissues accumulate latent mutations and suffer a decline in "immune fitness." Aging-related changes in the ECM and the accumulation of senescent cells create a pro-tumorigenic landscape that favors clonal expansion.
• Obesity: Obese adipocytes act as endocrine cells, creating a systemic imbalance between leptin (pro-proliferative/inflammatory) and adiponectin (reduced in obesity). This state promotes chronic inflammation and alters tumor metabolic signaling.
• Other Environmental Factors: Chronic systemic disruptions—such as pollution, microplastics, and smoking—act as "tumor promoters" that stimulate inflammatory responses and facilitate the acquisition of hallmark functions.

6. Future Frontiers: Diagnostics and Therapeutic Co-Targeting

The Hanahan framework is shifting oncology from descriptive biology to an actionable strategy of mapping and disrupting hallmark heterogeneity.

Mechanistic Digital Pathology

Advanced profiling is enabling the mapping of tumors in unprecedented detail:

• Pathology Foundation Models: Unsupervised training of neural networks using massive multi-omic datasets (single-cell RNA, spatial transcriptomics) allows for the identification of hallmark signatures that predict drug sensitivity.
• Liquid Biopsies: Tracking tumor-derived molecules and cells in the circulation provides a dynamic, non-invasive method for monitoring hallmark evolution and the emergence of adaptive resistance.

Hallmark Co-Targeting Strategy

To overcome the limitations of monotherapy, the 2025 corollary hypothesis advocates for hallmark co-targeting. By hitting "mechanistically independent" vulnerabilities, clinicians can "raise the bar" for adaptive resistance—attacking the tumor "by land, by air, and by sea."

Successful Co-Targeting Examples:

• VEGF Inhibitors + Immune Checkpoint Inhibitors (ICIs): Normalizing vasculature facilitates T cell homing while simultaneously blocking the immuno-evasive hallmark.
• VEGF Inhibitors + PARP Inhibitors: Exploiting the enabling characteristic of genome instability (via DNA repair inhibition) in the context of vascular targeting.
• BCL-2 Inhibitors + Epigenetic Reprogramming Agents: Disrupting resistance to cell death while simultaneously blocking the gene expression programs (e.g., DNA methylation) that allow cells to adapt.

7. Conclusion

The "Four Dimensions" framework—Capabilities, Enabling Characteristics, TME Cells, and Systemic Interactions—provides the conceptual clarity required to navigate the daunting complexity of cancer. This model reinforces the shift from treating cancer as a single genetic lesion to treating it as a dynamic, systemic ecosystem. The future of oncology lies in hallmark-guided drug combinations designed to preclude adaptive evolution, transforming cancer from a lethal malady into a manageable disease through sophisticated, multi-pronged therapeutic intervention.

1. Hanahan D. Hallmarks of cancer-Then and now, and beyond. Cell. 2026 Jan 29:S0092-8674(25)01498-9. doi: 10.1016/j.cell.2025.12.049. Epub ahead of print. PMID: 41616779. ↩