The immunotherapy revolution promised to transform oncology, yet a stark dichotomy has emerged. CAR-T therapy delivers remarkable complete responses in hematological malignancies—sometimes exceeding 80% in B-cell acute lymphoblastic leukemia—while its performance against solid tumors remains stubbornly disappointing. Objective response rates in epithelial cancers rarely breach 20%, and durable remissions remain exceptional rather than expected.

Into this therapeutic gap steps an older approach now experiencing a renaissance: tumor-infiltrating lymphocyte therapy. The FDA's 2024 approval of lifileucel for advanced melanoma marked a watershed moment, validating decades of iterative refinement originating from Steven Rosenberg's pioneering work at the National Cancer Institute. The clinical data are striking—durable responses in heavily pretreated metastatic melanoma patients who had exhausted checkpoint inhibitors and targeted therapies.

The divergence in efficacy between TIL and CAR-T approaches in solid malignancies reveals fundamental truths about tumor immunology that synthetic receptor engineering cannot easily circumvent. TILs represent endogenous immune responses that have already solved the formidable challenges of tumor recognition, trafficking, and microenvironmental survival. Understanding why this natural advantage persists—and how manufacturing innovations are amplifying it—illuminates the path forward for cellular immunotherapy against the cancers that kill most patients.

CAR-T therapy's Achilles heel in solid tumors lies in its fundamental architecture: a single synthetic receptor targeting one predetermined antigen. This approach works brilliantly when that antigen is uniformly expressed and essential for tumor survival, as with CD19 on B-cell malignancies. Solid tumors obey different rules entirely. Intratumoral heterogeneity means any given surface marker varies in expression across subclonal populations, creating immediate selection pressure for antigen-negative escape variants.

TILs bypass this vulnerability through sheer diversity. A typical TIL product contains T cells recognizing dozens to hundreds of distinct tumor neoantigens—the mutated peptides arising from somatic mutations unique to each patient's cancer. This polyclonal repertoire emerged through natural immune surveillance, with each specificity representing a T cell clone that successfully identified and expanded against a tumor-derived target. The redundancy is not inefficiency; it is evolutionary wisdom encoded in the adaptive immune system.

The mathematics favor breadth. When TILs simultaneously target fifty neoantigens, tumor escape requires concurrent loss or downregulation of all fifty—a combinatorial impossibility in most cases. Single-target CAR-T creates a binary selective pressure: tumor cells either express the target and die, or lose it and survive. Clinical data confirm this theoretical concern—antigen loss represents a dominant resistance mechanism in CAR-T failures against solid tumors.

Recent advances in neoantigen prediction have enhanced TIL selection strategies. Computational pipelines identify which tumor mutations generate immunogenic peptides, allowing enrichment for T cells with confirmed tumor reactivity. Rather than infusing the entire expanded TIL population, manufacturers can now select for clones demonstrating neoantigen recognition, concentrating the therapeutic payload while maintaining polyclonal diversity.

The polyclonal framework also addresses another limitation plaguing CAR-T in solid tumors: the absence of truly tumor-specific surface antigens. Most targetable markers in epithelial cancers—HER2, EGFR, mesothelin—also appear on healthy tissues, creating on-target off-tumor toxicity. TILs recognize mutated intracellular proteins presented via HLA molecules, accessing a target space of genuine tumor specificity that surface-directed CARs cannot reach.

Takeaway

Targeting multiple tumor neoantigens simultaneously through polyclonal TIL populations creates a therapeutic redundancy that makes immune escape through antigen loss mathematically improbable—an advantage single-target approaches cannot replicate.

The solid tumor microenvironment presents a hostile landscape that synthetic cellular therapies struggle to navigate. Dense stromal barriers impede physical access. Immunosuppressive gradients of adenosine, prostaglandins, and kynurenine metabolites paralyze effector function. Nutrient-depleted, hypoxic conditions starve infiltrating lymphocytes. Regulatory T cells and myeloid-derived suppressor cells actively terminate cytotoxic responses. CAR-T cells, engineered in artificial culture conditions, encounter this immunological wasteland unprepared.

TILs carry a profound advantage: they have already survived this environment. By definition, these cells successfully trafficked to the tumor, penetrated stromal barriers, and persisted despite immunosuppressive pressures. Natural selection within the tumor microenvironment has enriched for T cells expressing appropriate chemokine receptors, adhesion molecules, and metabolic adaptations. This evolutionary refinement cannot be replicated through synthetic engineering alone.

The trafficking problem illustrates this distinction clearly. CAR-T cells infused intravenously must somehow localize to tumor deposits scattered throughout the body. Without the appropriate chemokine receptor repertoire, they circulate aimlessly or accumulate in irrelevant tissues. TILs retain the homing programs that originally guided them to the tumor—CXCR3 for interferon-gamma-induced chemokine gradients, integrins for vascular extravasation, matrix metalloproteinases for stromal penetration.

Persistence represents another domain where natural selection confers advantage. TILs demonstrate remarkable longevity following infusion, with tumor-reactive clones detectable for years in responding patients. This durability reflects epigenetic programming acquired during chronic antigen exposure—the differentiation states, transcriptional networks, and metabolic configurations that permit sustained function in challenging environments. Ex vivo expansion protocols have improved to preserve these favorable phenotypes rather than driving terminal effector differentiation.

Combination strategies now leverage TILs' microenvironmental competence while addressing residual suppression. Checkpoint inhibitor co-administration releases the brakes that originally limited TIL efficacy. IL-2 supplementation supports survival and proliferation. Emerging approaches incorporate lymphodepletion regimens that reset the immunological landscape before TIL infusion, eliminating regulatory populations and creating cytokine availability for adoptively transferred cells.

Takeaway

TILs possess trafficking, persistence, and survival programs naturally selected through actual tumor infiltration—adaptations that synthetic CAR-T cells lack and that engineering approaches have not yet successfully replicated.

TIL therapy's historical limitation was never efficacy but manufacturability. Traditional protocols required 5-7 weeks of ex vivo expansion, yielded variable products, and failed outright in 15-20% of attempts. Patients with rapidly progressive disease died awaiting their cellular product. The path to broader adoption demanded manufacturing innovations that compressed timelines, improved consistency, and reduced cost.

Rapid expansion protocols now achieve therapeutic cell numbers in 16-22 days. Optimized culture conditions maintain T cell fitness while accelerating proliferation. Automated closed-system bioreactors reduce contamination risk and labor intensity. These advances transformed TIL manufacturing from an artisanal craft practiced at a few academic centers into a reproducible industrial process suitable for commercial scale.

Selection strategies have evolved beyond simple bulk expansion. Young TIL protocols harvest cells after minimal ex vivo culture, preserving favorable differentiation states at the cost of lower total numbers. Neoantigen-selected TIL products enrich for tumor-reactive specificities identified through mutation analysis and reactivity screening. These approaches concentrate therapeutic activity while potentially reducing the infused cell mass required for efficacy.

Genetic modification opens new possibilities for enhancing TIL function. CRISPR-mediated knockout of inhibitory receptors like PD-1 prevents microenvironmental suppression. Introduction of membrane-bound IL-15 provides autocrine survival signals. Deletion of the TGF-beta receptor renders TILs resistant to a major immunosuppressive cytokine in the tumor microenvironment. These modifications layer engineered advantages onto the natural capabilities TILs already possess.

The manufacturing evolution also addresses the tumor supply problem. Not all resected tumors yield adequate TIL populations—some are too necrotic, too small, or too sparsely infiltrated. Alternative sources including tumor-draining lymph nodes and peripheral blood neoantigen-reactive T cells expand the eligible patient population. These innovations divorce TIL therapy from its historical dependence on accessible, resectable tumor tissue.

Takeaway

Manufacturing advances have transformed TIL therapy from a weeks-long artisanal process into a reproducible 16-22 day protocol, while genetic modifications now enhance natural TIL capabilities rather than attempting to recreate them synthetically.

The comparison between TIL and CAR-T therapy in solid tumors ultimately reflects a deeper truth about immunological engineering: billions of years of evolutionary refinement are difficult to surpass with decades of biotechnology. TILs represent natural solutions to problems that synthetic approaches are still learning to articulate—antigen heterogeneity, microenvironmental hostility, trafficking requirements, persistence needs.

This does not render CAR-T obsolete for solid tumors. Next-generation approaches incorporating armored CARs, dual targeting, and synthetic biology circuits may eventually overcome current limitations. The field advances rapidly, and today's constraints often become tomorrow's solved problems.

Yet for patients with advanced solid malignancies today, TIL therapy offers something CAR-T cannot: proven efficacy where it matters most. The manufacturing innovations enabling broader access, combined with selection strategies amplifying natural capabilities, position TIL therapy as the cellular immunotherapy approach best suited for the cancers that constitute the majority of oncological mortality. Evolution, it seems, remains a formidable engineer.