Market Landscape
1. Where is the global landscape heading? Larger, younger, and more uneven
Overall scale continues to expand. Scenario projections from the International Agency for Research on Cancer (IARC) and the World Health Organization (WHO), based on GLOBOCAN, indicate that by 2040 colorectal cancer (CRC) will account for approximately 3.2 million new cases and 1.6 million deaths annually. Although incidence has declined in some high-income countries owing to screening programs, it is rising in transitioning economies and among younger populations, leading to a substantial increase in the global burden.
Figure 1. Global CRC New Cases and Deaths Projection (2020-2040)
Data sources: IARC's GLOBOCAN database and WHO colorectal cancer fact sheet
A younger shift is creating additional demand. Authoritative multi-country data show a sustained rise in early-onset CRC (diagnosed before age 50). Among 50 countries/regions evaluated, 27 report increasing early-onset incidence, and in many settings the growth outpaces that observed in older adults. This structural shift will bring forward—and amplify—needs for screening, treatment, and post-treatment surveillance.
Figure 2. Regional Disparities in CRC Screening Coverage and Late-Stage Diagnosis Rates
Data source: World Health Organization (WHO) screening reports
Regional disparities & stage migration: In low- and middle-income countries (LMICs), low screening penetration and constrained access lead to a higher proportion of late-stage diagnoses and elevated case-fatality rates. Systematic reviews and policy evaluations consistently indicate that CRC screening remains a substantially unmet public-health need in LMICs. This implies that future incremental patient growth and healthcare resource utilization will increasingly be concentrated in emerging markets.
Macro drivers—aging, urbanization, and lifestyle change: Population aging, urbanization, and shifts in lifestyle—rising obesity, greater consumption of ultra-processed foods, sedentary behavior, and alcohol/tobacco use—will continue to heighten risk exposure and reinforce a long-term upward demand trend.
Figure 3. Trend of Early-Onset CRC (2000-2020)
Data source: PubMed (NCBI) studies
Summary: By around 2040, colorectal cancer (CRC) will exhibit a triple pattern—expanding overall burden + rising early-onset incidence + persistent regional inequities—which will directly catalyze dual upgrades in the scale and quality of diagnostics, care pathways, and the therapeutics market.
2. Implications for the therapeutics market: growth amid "small eligible populations + limited benefit + poor access"
The CRC treatment market is expected to grow steadily, though estimates vary: multiple independent sources place the global CRC therapy CAGR at 4.5%–7.8%, with market size commonly forecast at USD $18–26.5 billion by 2032–2034.
Immunotherapy delivers the greatest benefit in the dMMR/MSI-H subgroup, which accounts for 4%–5% of metastatic CRC; nonetheless, primary and acquired resistance remain significant challenges.
Figure 4. Molecular Subgroups and Survival in mCRC
Data sources: Frontiers and U.S. SEER database
Targeted options remain niche, with resistance curbing impact. The recently approved combination of a KRAS G12C inhibitor plus anti-EGFR therapy applies to only ~3–5% of patients by molecular profile. The small eligible subgroup, together with primary and acquired resistance, constrains real-world population-level benefit.
Survival bottlenecks and late-stage presentation. SEER staging data indicate that 23% of U.S. CRC cases are diagnosed at a distant stage, where the 5-year survival rate is just 16%. Consistent with multiple global reviews and guidelines, ~20% present with de novo metastatic disease at diagnosis, and an additional 20–30% of patients initially staged as early disease subsequently develop metastases.
Figure 5. 5-Year Survival Rates by CRC Stage
Data source: U.S. SEER Program
Delivery and penetration: a common ceiling in solid tumors. Abnormal vasculature, elevated interstitial fluid pressure, a dense stromal matrix, and heterogeneous perfusion collectively result in inadequate drug distribution to the tumor core. This bottleneck not only limits the efficacy of cytotoxic chemotherapy, but also reduces tissue exposure and durability for targeted agents, immunotherapies, and even nanomedicines—constituting a central systems-level barrier to translational efficiency.
Figure 6. Solid Tumor Delivery Barriers (Conceptual Schematic)
Conclusion. Even in a steadily expanding commercial arena, four constraints continue to define a large unmet need: small eligible populations, limited benefit beyond early lines, toxicity and access barriers, and tumor-microenvironment (TME) delivery bottlenecks. Players able to deliver drugs safely and reliably into the deep tumor compartment—while expanding the addressable population—are positioned to capture outsized returns in the 2030–2040 market segmentation.
Current Challenges
Conventional chemotherapy: high non-selective toxicity + rapid resistance + delivery/adherence hurdles
Nonselective systemic toxicity:
Fluoropyrimidine regimens containing oxaliplatin or irinotecan remain the therapeutic backbone for mCRC. However, oxaliplatin-induced peripheral neuropathy is a dose-limiting adverse event that often necessitates dose reduction or discontinuation, directly undermining the durability of benefit and patients' quality of life.
Pervasive resistance mechanisms:
Upregulation/amplification of thymidylate synthase—the principal target of 5-FU—is closely associated with acquired resistance; in parallel, dihydropyrimidine dehydrogenase (DPD)–mediated catabolism contributes to failure of first-line and adjuvant therapy. In addition, multidrug efflux pumps (e.g., P-glycoprotein) reduce intracellular exposure to multiple chemotherapeutics and are key drivers of multidrug resistance (MDR) in CRC.
Administration & adherence:
Standard FOLFOX/FOLFIRI regimens require 46–48 hours of continuous IV infusion of 5-FU (repeated every 14 days), imposing substantial time costs and burdens related to venous access and pump management. "Oral 5-FU" suffers from rapid first-pass metabolism via DPD, resulting in low and highly variable exposure; in clinical practice, prodrug formulations are used to circumvent this issue.
Insufficient intratumoral delivery:
Abnormal vasculature, dense stroma, and elevated interstitial fluid pressure in solid tumors keep drug concentrations in deep tumor regions chronically subtherapeutic, limiting both tissue exposure and the uniformity of cytotoxic effect.
The crux:
Chemotherapy's combination of systemic administration + nonselective cytotoxicity drives a vicious cycle of toxicity → dose reduction → resistance, while inadequate deep penetration remains a persistent systems-level bottleneck.
Targeted therapies: molecular heterogeneity + narrow eligibility + poor tumor penetration
Tiny, fragmented eligible populations:
Clinical benefit from anti-EGFR monoclonal antibodies (cetuximab/panitumumab) in first-line mCRC is concentrated in left-sided, RAS-wild-type disease; efficacy is weaker in right-sided tumors or RAS-mutant populations. HER2-positive mCRC accounts for only ~2–5%; although regimens such as DS-8201 (trastuzumab deruxtecan) and tucatinib + trastuzumab exist, the overall indication remains very narrow.
Inherently limited deep-tissue penetration:
Full-length antibodies in solid tumors are constrained by vascular permeability, stromal barriers, and diffusion distance, leading to slow, heterogeneous tissue distribution and difficulty achieving effective concentrations in tumor cores.
"Having a target ≠ delivering a drug well":
Even with "EGFR/CD44-targeted nanocarriers," cross-expression in normal tissues and TME heterogeneity can produce off-target exposure, while the effective tumor-delivered dose of nanomedicines has long been shown to have a median below 1% of the injected dose; the fraction that actually reaches tumor cells is even lower.
Figure 8. Small Eligible Subgroups in mCRC
Data source: ESMO Open
Immunotherapy: narrow indications + low monotherapy activity in MSS + immune toxicity and infusion burden
Narrow indications: In mCRC, dMMR/MSI-H accounts for only ~4–6% of patients. This subgroup derives marked and durable survival benefit from PD-1 inhibitors, but its small size limits overall impact.
Limited efficacy in the mainstream population: The MSS/pMMR majority shows ~0–5% objective response to PD-1/PD-L1 monotherapy. Numerous studies and reviews indicate that single-agent IO is unlikely to meaningfully shift outcomes in MSS mCRC; combination strategies are under exploration, but results remain inconsistent and often subgroup-dependent.
Immune-related adverse events (irAEs): While generally manageable, colitis, thyroid/pituitary endocrinopathies, and pneumonitis can necessitate treatment interruption and corticosteroids. Meta-analyses report any-grade irAEs ≈60%+ and grade ≥3 ≈14%. Outpatient regimens typically require IV infusions every 2–3 weeks, and the ongoing infusion schedule plus toxicity management imposes burdens on both patients and healthcare systems.
Figure 9. CRC 5-Year Survival by Stage
Data source: American Cancer Society
Unmet need motivating our approach. Chemotherapy is constrained by non-selective toxicity, resistance, and inadequate deep-tumor delivery; targeted therapy by molecular heterogeneity and poor tissue penetration; and immunotherapy by narrow indications, low monotherapy activity in MSS disease, and immune toxicities plus infusion burden. Together, these define the gap we intend to address.
Our Advantages
Sharper targeting: Dual lock: TME × cancer-cell surface charge/gangliosides
Cancer-cell–selective entry pathway. BR2 derives from the antimicrobial peptide BF2 and contains a transmembrane motif. After interacting with gangliosides enriched on cancer-cell membranes, it enters cells via lipid-mediated macropinocytosis. Compared with "generic CPPs," it is gentler toward normal cells and exhibits stronger selectivity—providing the biophysical basis for our second lock at the cancer-cell level.
TME-activated first lock. An MMP-2/9–cleavable linker couples the cationic penetrating segment to a polyanionic shielding peptide, forming an TRACER "molecular switch." Cleavage and deshielding occur only within the tumor microenvironment (where MMP-2/9 are overexpressed), thereby restoring penetrability at the lesion site. This strategy has been repeatedly validated in systematic reviews and in imaging/drug-delivery studies, and is a mature engineering approach to enhance selectivity and tissue penetration.
Figure 10. Programmable Safety Window via TRACER Activation
Data source: Proceedings of the National Academy of Sciences (PNAS)
Why CRC: Matrix metalloproteinases MMP-2/9 are closely linked to invasion, metastasis, and poor prognosis in colorectal cancer (CRC). Their elevated enzymatic activity at lesion sites provides an exploitable biological "anchor." This makes the TRACER-IL24 design—activation restricted to the tumor microenvironment—both more probable and better aligned with real CRC pathophysiology.
Key takeaway: Our approach is not passive accumulation but a dual-lock strategy combining context-triggered activation and cell specificity. The TME determines where activation occurs ("unlocking"), while cancer-cell membrane charge and ganglioside enrichment determine which cells internalize via macropinocytosis. Acting together, these two locks increase the likelihood of achieving therapeutically relevant concentrations deep within the tumor.
Safer, more controllable
Poly-anionic "molecular switch" to widen the therapeutic window and reduce systemic toxicity.
Programmable shield → activation: In circulation, the poly-anionic shielding segment of TRACER-IL24 suppresses nonspecific interactions between the cationic penetrating peptide and cell membranes. Once at the lesion, MMP-2/9 cleavage removes the shield, restoring penetration and delivery capacity. This "closed-then-open" sequence effectively converts systemic activity into site-localized activity.
Versus conventional and nano-delivery approaches.
Literature reviews indicate that the median fraction of injected nanomedicines reaching solid tumors is ~0.7%, and many "targeted" systems still fail to establish stable exposure in tumor cores—narrowing the therapeutic window. By unmasking in situ at the lesion, TRACER is poised to shift the dose–toxicity trade-off toward equivalent intratumoral exposure with a lower C_max, thereby easing systemic burden.
Superior patient experience: Smart microneedle patch = painless at-home dosing × steady-state release × improved adherence
Addressing three patient pain points simultaneously. Intravenous pumps, frequent outpatient visits, and needle phobia can all be mitigated by microneedle patches: painless/minimally invasive, suitable for self-administration, and easy to standardize dosing. Multiple recent narrative/systematic reviews and clinically oriented overviews indicate that microneedles have real-world potential for at-home self-dosing and adherence gains, especially in chronic/repeat-dosing settings.
Compatible with peptides/nanosystems. Studies have already combined nanoparticles × dissolving microneedles for transdermal delivery of anticancer agents. This pairing can bypass the GI tract and first-pass metabolism, create a subcutaneous drug depot with a sustained-release profile, and reduce infusion-related resource utilization.
An amplifier for our carrier. Microneedles first "plant" the TRACER–IL24 accurately and quantitatively into the dermal vasculature and immune-cell–rich zones, reducing first-pass effects and C_max-driven systemic discomfort. TRACER-IL24 is then enzymatically activated at the tumor site, converting systemic exposure into lesion-focused exposure—thereby achieving system-level optimization of pharmacokinetics and tissue distribution.
Operationalizing the synergy of "smart carrier × smart device"
Cleavable-linker sequence library: Use PLGLAG and other MMP-2/9–preferred motifs as starting points; perform positional scanning and stereochemical fine-tuning to balance cleavage rate, specificity, and in vivo stability. Where appropriate, introduce motifs with MMP-2 > MMP-9 preference to match tumor subtypes.
Design of the polyanionic shielding segment: Employ poly-glutamate / poly-aspartate tracts or removable counterion-pairing peptides as an electrostatic "mask," drawing on recent counterion shielding strategies to conditionally gate CPP–membrane interactions.
Microneedle device pathway: Prioritize dissolving/encapsulating designs and validate mechanical strength and intradermal disintegration parameters. From a dosing perspective, define the operating window for (drug load per patch) × (dissolution time) × (intradermal residence), and map these to in vivo TRACER activation and depth of intratumoral penetration.
Competitive comparison
Versus passive targeting / conventional nanomedicine: These approaches suffer from limited deep-tumor penetration, with a median intratumoral delivery of only ~0.7% of the injected dose, and are highly sensitive to TME heterogeneity. By contrast, our design combines lesion-site activation with cell-level macropinocytic uptake, increasing the share of drug that effectively reaches tumor cores.
Versus monoclonal antibodies (mAbs) / ADCs: Full-length antibodies have large molecular weights and diffuse slowly, leading to suboptimal concentrations in deep tumor regions; ADC development in CRC also faces a narrow pool of actionable targets and complex trade-offs with off-target toxicity. Our short-peptide + programmable shielding strategy aims for more uniform tissue distribution and a tunable therapeutic window.
Versus IO monotherapy / selected combinations: Indications are concentrated in the MSI-H minority, while MSS patients show very low ORR to single-agent PD-1/PD-L1 and require repeated infusions. Our pathway focuses on the delivery dimension, improving tissue exposure and the efficacy baseline for a broader patient population.
Figure 11. Competitive Landscape (Optimized Radar)
Dimensions: Deep Penetration, Selectivity, Eligible Population, Convenience, Safety Window
